Born in Paris, de Guebriant joined the Paris Foreign Mission Society (PFMS) in 1883 and two years later was ordained and sent to China. In 1910 he became the first vicar apostolic of Kientchang (Xichang), Szechwan (Sichuan) Province, and then was moved to the seat of Canton (Guangzhou) in 1916. In 1918 he was one of six missionary bishops selected by Cardinal Van Rossum, prefect of the Propaganda Fide, to answer a questionnaire on the situation of the church in China.
In the November 1919 encyclical Maximum illud from Pope Benedict XV, several directives echo points made by de Guebriant: for instance, choosing heads of mission with good leadership skills, improving the language proficiency of missionaries, forming a native clergy on a par with foreign missionaries, and freeing the Catholic Church in China of its foreign character. Van Rossum also followed up on two other recommendations made by de Guebriant: sending an apostolic visitor to tour all the China missions, and naming a permanent representative of the Holy See in Peking (Beijing). In July 1919 de Gudbriant found himself appointed apostolic visitor in missiones sinensis, and in August 1922 Archbishop Celso Costantini was appointed the Vatican's first apostolic delegate to China.
Following a reorganization of the PFMS in accordance with the Code of Canon Law promulgated by the Holy See in 1917, in 1921 de Guebriant became the first to assume the responsibility of superior general of his society. During his 14-year term, he ended his society's monopoly over large mission fields by partitioning them and inviting other missionary groups to assume the evangelization of some of these smaller territories. He also began implementing the policy that missioners who were pioneers should move on once a local church had been established in a particular place. Two high points of his life were viewing the ordination of the first six Chinese bishops in Rome by Pope Pius XI (1926) and joining Archbishop Costantini at the Temple of Heaven in Peking in reciting the Pater Noster (1932).