De Souza joined the Society of Jesus (Jesuits) in 1712. In 1724 Emperor Yongzheng banned Christianity and deported all missionaries to Macau, except those in the calendrical bureau and others working in Beijing who were housed in the South Church, East Church, and North Church. In 1726 the Portuguese king, John V, officially sent Allexande Metello to China. Accompanying him were three Portuguese Jesuits, one of whom was de Souza. They were granted audiences with Yongzheng in Beijing on 28 May and 8 Jul 1727.
Before leaving Beijing on 16 Jul, Metello recommended the three Jesuits with expertise in calendrical matters to the emperor, who subsequently hired them. De Souza engaged in clandestine religious work and learned of his appointment as bishop of Beijing (Episcopus Pekinensis) on 19 Dec 1740. He was consecrated in Macau and returned to Beijing.
In 1742 Pope Clement XIV issued the final bull prohibiting the practice of Chinese rites, the Ex Quo Singulari. De Souza announced it only in 1744 through a pastoral letter and notices in the three churches in Beijing, after strong urging from the Vatican.