In a statewide population of 375,000, there were about ten thousand Catholics, the majority concentrated in Vicksburg, Natchez, and along the Gulf Coast. For Catholics, there were no churches, nor Catholic institutions of any kind at all. The only priest in the state was there temporarily, on loan from another diocese. Without money or resources,  the new bishop started his diocese from scratch.

In time, however, he introduced an academy for young women, the first Catholic school of any kind in the state, run by laywomen. Two of his nieces came from Maryland to teach there. In February 1842, he dedicated the cornerstone for a cathedral in Natchez, "The Transfixed Heart of the Blessed and Immaculate Mary Ever Virgin" (now known as St. Mary's Basilica). He traveled throughout the state, celebrating Mass in private homes, town halls, even Methodist meeting-houses. In this predominantly Protestant state, he won over the good will of his non-Catholic neighbors. One historian writes:

Dr. Chanche was an eloquent preacher, a profound theologian, and a man of fine administrative abilities. He was tall, commanding, and handsome in his appearance, and in the performance of the sublime ceremonies of the altar he was particularly imposing and distinguished... He was urbane and cultivated in his manners, always accessible, courteous, and kind, and there were few clergymen in his day who had more numerous or more ardent friends and admirers among the Bishops, clergy, and laity.

A popular preacher, he was even asked to preach to Protestant audiences. The Mississippi Free Trader called him a "finished and ripe scholar... a dignified prelate."

Among his fellow bishops, Chanche was a highly respected figure. In May 1852, he attended the Second Plenary Council of Baltimore, a national gathering of the American bishops. However, he died of cholera in Frederick, Maryland, on July 22, 1852, and was buried in Baltimore's Cathedral Cemetery. In August 2007, his remains were re-interred at the cathedral he had built in Natchez (according to his original wish).

In 1848, he had brought the first Catholic nuns to Mississippi, the Sisters of Charity. Soon they opened a school and orphanage. By the time of the bishop's death, there were eleven priests in the state, along with eleven parishes and thirty-two missions. He had also started an outreach to African-American Catholics.

Over the course of only eleven years, Bishop Chanche created the framework for Catholic life in a state and, as one historian notes, he "inaugurated a happier day for religion in Mississippi."