In 1718, Jean-Baptiste Le Moyne, Sieur de Bienville, Governor of Louisiana, founded the city of New Orleans for King Louis XV of France. According to sources, as Bienville planned the city, he used his sword to trace the site to be occupied by the parish church, and soon afterward, a wood and adobe church was erected under the patronage of the French government. It was named the Church of St. Louis in honor of the king, and placed under the Diocese of Quebec. The first rector was Prothais Boyer, a missionary of the Order of Friars Minor. In September 1723, a hurricane devastated the colony and completely destroyed the Church of St. Louis. Church services were held in several makeshift locations until a proper church was built, including a former tavern located between St. Louis and Toulouse streets.

Architect Adrien de Pauger designed and began constructing the first permanent Church of St. Louis, built of brick between posts. De Pauger died before the church was completed. In his will, he requested that he be buried within the unfinished building, a request that was presumably granted, making him among the first of many to be buried within church grounds. In December 1727, after four years of construction, Father Raphaël de Luxembourg, Capuchin priest and fifth rector of the Church of St. Louis, dedicated the first permanent church.

In the mid-1750s, to ensure the good condition and the daily ministries of the church, a group of laymen called Marguilliers, or churchwardens, began managing the affairs of the Church of St. Louis in the name of the crown. As a colony of France, New Orleans was infused with distinct Catholic identity. The church echoed the chant of Te Deum for royal births, new kings, victorious battles, and for the feast day of the governor's patron saint. Feast days and Holy Week were celebrated with particular pomp, as they were in France. These customs continued even after New Orleans came under Spanish rule.

In 1763, Louisiana became a Spanish colony. In the early years of Spanish rule, the Church of St. Louis fell into a state of disrepair. Services were temporarily held in a warehouse on Dumaine Street until necessary repairs were made. In 1769, General Alejandro O'Reilly, the new Spanish governor, attended a Benediction and singing of the Te Deum at the newly repaired church. In the same year, Father Antonio de Sedella, known by most as Père Antoine, arrived to begin a contentious pastorate of more than forty years.

On Good Friday, March 17, 1788, a fire broke out in a private chapel on Chartres Street. Citizens who detected the fire went to Père Antoine asking him to ring the church bells to signal the bucket brigade and alert the colonists. Père Antoine denied their request, declaring Good Friday as a day of penance and solemnity, not a day for bells, which are a sign of joy. He insisted they go from door to door to alert people. Despite citizens' best efforts, the fire raged uncontrollably. When the conflagration threatened the rectory, Père Antoine sent many of the church records to the Director of Tobacco's house for safe keeping. Before all of the books were transferred, he was informed that the Ursuline Convent was in danger. Père Antoine threw the remaining records out of the window and ran aid the nuns. The Ursuline Convent was spared damage from the fire through the nuns' prayers to Our Lady. The director's house burned and the records that were sent there were destroyed. Only the records thrown from the window survived the blaze. The fire destroyed eighty percent of the city, including the Church of St. Louis, which was completely decimated.

Don Andres Almonester y Roxas, a native of Andalusia, royal notary, judge, colonel of the militia, and prolific property owner, offered to rebuild the Church of St. Louis on the condition that Mass be said weekly for the repose of his soul and bells be rung to remind people to pray for him in perpetuity. In 1789, the cornerstone of the new church was laid, and five years later the new church was completed.

In 1793, the vast Diocese of Louisiana and the Floridas was created, encompassing what would become the entire Louisiana Purchase territory and the peninsula of Florida. From the ashes of the Church of St. Louis rose the St. Louis Cathedral, which served as the central church of the new diocese. The cathedral is the seat of the bishop, where his cathedral is placed, and from where he ministers to his See. Luis Peñalver y Cárdenas of Havana, the first bishop of New Orleans, arrived in July 1795 to take formal possession of his See and begin his episcopal duties.

The new St. Louis Cathedral, designed by Gilberto Guillemard, was completed in the fall of 1794. It had a low-flat roof flanked by bell-capped hexagonal towers, but it lacked a central spire. The church bells, baptized St. Joseph and St. Anthony, were cast in Havana, and placed in the towers in July of 1804. In 1819, Benjamin Henry Bonneval Latrobe, architect of the United States Capitol building, was selected to construct a new central tower that would house a clock imported from France. After Latrobe's death from yellow fever in 1820, Leriche undertook the task of having the clock installed.

By 1800, New Orleans was one of North America's most cosmopolitan cities. The majority of the New Orleans Catholic community was native born, but sacramental records depict a diverse city. Immigrants from France, Spain, the Canary Islands, Cuba, Mexico, Bohemia, Italy, Canada, Scotland, Jamaica, Martinique, Flanders, Ireland, and the African continent are among those who married or whose children were baptized at the St. Louis Cathedral. In 1800, over 700 people were baptized at the Cathedral. For more than a century, the Church of St. Louis and its successor, the St. Louis Cathedral, was the only Catholic Church in the City of New Orleans. This venerable place continues to serve as the center of Catholicism in the city.

In 1835, Antoine Blanc was appointed bishop of the Diocese of New Orleans. At the time of Bishop Blanc's appointment, there were twenty-six churches and only twenty-four priests. In 1838, to meet the growing need for priests, Bishop Blanc established the College of St. Charles in Grand Couteau and the Seminary of St. Vincent de Paul in Plattenville. By the 1840s, many clergy felt the churchwardens, who handled the daily ministries of the cathedral, had become too powerful. This culminated in 1842, when a bitter public controversy broke out between Bishop Blanc and the churchwardens, after the latter refused to accept the bishop's appointee for rector of the cathedral. In 1844, the Louisiana Supreme Court decided in favor of Bishop Blanc, giving him full appointment power and limiting the churchwardens' authority.

In March 1849, Irish builder John Patrick Kirwan was hired to remodel and enlarge the cathedral in order to create a more modern building impressive enough to assert the continued importance of the "Old Quarter." To accomplish this, the churchwardens hired the most notable French-born architect working in the city: J. N. B. de Pouilly. Although the project was termed a "restoration," the cathedral was essentially demolished, due to a massive construction accident that brought down the central tower and portions of the walls, leaving only the lower portions of the front wall.

In 1850, the Diocese of New Orleans was raised to an archdiocese, and Bishop Blanc was elevated to archbishop. On December 7, 1851, Archbishop Antoine Blanc blessed the new cathedral in a colorful public ceremony that included seven companies of 300 uniformed men, a procession from the Old Ursuline Convent to the Cathedral, and a twenty-one-gun salute.

As New Orleans grew and became more diverse, the twentieth century brought new challenges and opportunities to the city and the cathedral. On April 25, 1909, an explosion near the cathedral's entrance shook the building and the city to its core. Stained-glass windows shattered into the streets. Chaos followed as panicked people ran from the cathedral, curious bystanders assembled to witness the destruction, and policemen, firemen, and the city's best detectives gathered to investigate. A nitroglycerin bomb had been placed in the choir loft. Miraculously, no one was injured. Two men were arrested for the bombing, but the charges were dropped. The true identity of the culprits and their motive remains a mystery.

On September 29, 1915, a Category-4 storm struck New Orleans and raged from dawn into the night. Roofs were blown off buildings—the Presbytère on Jackson Square even lost its cupola—yet the exterior damage to the cathedral was limited to one spire. Many of the city's Catholic Churches, including St. Mary's Church at the Ursuline Convent, faced a far worse fate. Despite escaping immediate damage from the hurricane, the cathedral walls weakened, due to major soil subsidence (caused by damage to the city's subsurface drainage). The building was condemned and forced to close after Mass on Easter Sunday 1916. With the help of an anonymous donor, extensive repairs were completed, and the interior was redecorated by fresco artist John Geiser. In 1918, as the city marked the two-hundredth anniversary of its founding, the local church also celebrated its two-hundredth anniversary of Christianity in the Louisiana province. The church was marked as the mother church, the cradle of Christianity in the Mississippi Valley.

On December 9, 1964, Pope Paul VI elevated St. Louis Cathedral to the rank of minor basilica, citing its antiquity, grandeur, myriad historical events, and its place as "a center of effective piety and pastoral zeal." In preparation for the designation of minor basilica, Archbishop John Cody consecrated the cathedral on December 8, during which he anointed the walls in twelve places. The privileges granted to minor basilicas are: the use of the basilican bell, a modified version of the tintinnabulum granted to major basilicas and the use of the basilican pavilion, or umbrella, made of scarlet and yellow silk. Minor basilicas enjoy privileges by implication or by custom, such as precedence over other churches in processions, a coat-of-arms and a corporate seal. For over a year and a half, the church was called "The Basilica of St. Louis, King of France." On July 19, 1966, Archbishop Philip Hannan restored the beloved name held dear in the hearts of New Orleanians: St. Louis Cathedral.

In September 1987, Pope John Paul II visited New Orleans and celebrated Mass at the cathedral. After Mass, there was a parade through the French Quarter in celebration of His Holiness's visit. Throughout the history of the city, New Orleanians have welcomed the famous and infamous. A pope, generals, presidents, prime ministers, kings, and emperors have all visited this venerable edifice. Common people and the elite, have worshipped side by side in this sacred House of God. In times of great desperation or joyous celebration, the St. Louis Cathedral has and continues to open its doors to all who seek peace, mercy, and solace. The cathedral is the symbol of Catholicism and an icon of the Crescent City.

Most Reverend Gregory M. Aymond is the fourteenth Archbishop of New Orleans and the first New Orleans native to serve as the Shepherd of the local Catholic Church in the city's 300-year history. Today, the Archdiocese of New Orleans ministers to over half a million Catholics in the city of New Orleans and seven surrounding civil parishes. It serves as the Metropolitan See over the Province of Louisiana, which includes the Dioceses of Alexandria, Baton Rouge, Houma-Thibodaux, Lafayette, Lake Charles, and Shreveport. The Catholic faithful of the archdiocese worship and receive sacraments in 111 parishes, and over 35,000 children are educated in eighty Catholic schools. The social outreach ministries of the archdiocese serve as the face and hands of Christ to the city's poor and most vulnerable and bring hope in times of despair.

It is from the small wood-framed Church of St. Louis, set in the crescent of the mighty Mississippi River in 1718, that this living and thriving church was born. Today, "the native son" shepherds his flock from the iconic altar of St. Louis Cathedral and beyond. Modern technology has made Mass from the historic cathedral available through broadcast and digital media. There is, perhaps, no more identifiable icon or symbol of New Orleans than the St. Louis Cathedral. With its doors open to Jackson Square and its spires raising eyes to the heavens, the Church in the Crescent is a living witness to 300 years of Catholicism in New Orleans.