In 1853, James Oliver Van de Velde, former president of St. Louis University, then serving as Bishop of Chicago, was transferred to Natchez by Pope Pius IX to become the second bishop of the Diocese.

Bishop Van de Velde arrived in Natchez at a tragic time — the outbreak of a yellow fever epidemic in the region, which killed some 750 people in Natchez and more than 7,800 in New Orleans. The former president of St. Louis University, Bishop Van de Velde moved quickly to continue the work of Bishop Chance. One of his accomplishments was to gather the bones on the surface of the ground at the old Spanish cemetery and deposit them in a crypt under the sanctuary of St. Mary Cathedral. He also oversaw the installation of a slate roof on the cathedral.

Another milestone for the Catholic Church in Mississippi occurred in 1855 with the opening of St. Stanislaus College in Bay St. Louis by Father Stanislaus Buteux, pastor of Our Lady of the Gulf Parish. Five Brothers of the Sacred Heart served as the faculty.

Tragically, Bishop Van de Velde contracted yellow fever and died in 1855, as did 40 parishioners. Buried in the crypt beneath the cathedral, his remains were moved in 1874 to Jesuit Cemetery in Florissant, Missouri.

Bishop R. O. Gerow would write in Catholicity in Mississippi that Bishop Van de Velde “entered zealously upon the work of extending the kingdom of God in other portions of his diocese. Eapecially to be noted are his most successful efforts to induce the Sisters of St. Joseph of Bourg to open a school in Bay St. Louis.”