He devoted himself from his earliest youth to the ecclesiastical state, while his brother Cæsar Choiseul du Plessis-Praslin entered a military career.
He was consecrated bishop of Comminges in 1644, and at once set about visiting his diocese, restoring discipline among the clergy, and establishing schools and colleges.
When, in 1651, the majority of the French bishops petitioned Pope Innocent X to decide upon the ten propositions of Jansenius, Choiseul was among the eleven who requested no decision in the case.
When Choiseul saw that Jacques-Bénigne Bossuet's conciliatory distinction between the Holy See's infallibility in teaching the Catholic faith and its indefectibility in holding it found favour with both clergy and Court, he resigned his special commission.
Choiseul approved the French translation of a little book published in Cologne under the title "Monita salutaria Beatæ Mariæ Virginis ad cultores suos discretos".