It covers the following civil parishes: Avoyelles, Rapides, Vernon, Natchitoches, Winn, Caldwell, Madison, Franklin, Tensas, Concordia, Catahoula, LaSalle, and Grant.

In 1717, Margil made contact with Adayes Native Americans living near Spanish Lake in what is now Sabine Parish.

Leaving a Reverend Gusman in charge of the mission, Margil journeyed on foot to Natchitoches to minister to the French Catholics there, then returned to Texas.

In 1718, during a brief war with Spain, French soldiers plundered the Adayes mission, stealing the church vestments and scaring off the congregants.

[3] The Vatican in 1793 established the Diocese of Louisiana and the Floridas, covering a large sections of land in the American South.

By 1840, Reverend John Timon, then prefect apostolic of the Republic of Texas, was making regular visits to missions in northern Louisiana.

During this time period, a Reverend O'Brien, a Dominican priest from Louisville, was visiting Catholics living along the Mississippi River every year.

During his 22-year-long tenure, Martin recruited priests and religious from Europe for the diocese, established a seminary to train native clergy, founded numerous missions, and erected a cathedral.

[8] He invited several religious orders to the diocese, such as the Sisters of Divine Providence, the Carmelites, and the Jesuits, who established schools in Alexandria, Mansfield, and Shreveport, all in Louisiana.

[8] After Durier died in 1904, Pope Pius X named Reverend Cornelius Van de Ven as the next bishop of Natchitoches.

Van de Ven recruited the Sisters of Charity of the Incarnate Word to the diocese, where they established North Louisiana's first Catholic hospital (Schumpert Medical Center in Shreveport) and St. Joseph's orphanage.

To replace Desmond, Pope Pius XII appointed Reverend Charles Greco of New Orleans as the next bishop of Alexandria.

In 2004, Monsignor Ronald Herzog of the Diocese of Biloxi was appointed Bishop of Alexandria in Louisiana by John Paul II.

[17] The diocese in 2006 suspended Reverend Frederick Lyons, a retired priest, from ministry after receiving allegations from two individuals that he sexually abused them as minors.

[18] In November 2023, the Congregation for the Doctrine of Faith ordered Lyons to follow a life of prayer and penance and stripped him of this title of protonotary apostolic supernumerary.

[19] The diocese in March 2013 removed Reverend Jamie Medina-Cruz from his post at St. Mary's Assumption Church in Cottonport after he was arrested on charges of sexual misconduct with a minor.

[25] Reverend Theodore Lelieveld was added to the clergy list in September 2019 after sex abuse allegations against him from the 1960s were deemed credible.

[26] In October 2024, the diocese announced that it was preparing to file for Chapter 11 bankruptcy protection as it continues to face several sexual abuse lawsuits.