Mendes was born in Santo Aleixo. He entered the Society of Jesus, where he was ordained priest, he received his doctorate in theology at the University of Coimbra, where he subsequently taught at the College of Arts. In response to the favor Emperor Susenyos of Ethiopia showed towards Catholicism, Mendes was appointed Patriarch of Ethiopia by Pope Urban VIII, and left for Ethiopia in March 1623.
The journey to Ethiopia was long and difficult. Mendes' party reached Portuguese Mozambique that September, where they were delayed by winter weather, and only reached Goa on 28 May 1624. After making further preparations in Goa, the Patriarch sailed for Beilul by way of Diu (where he was joined by Jerónimo Lobo), and arrived at Beilul on 2 May 1625. This port on the Red Sea was controlled by the king of the Afars, who was a vassal to the Emperor of Ethiopia; the primary port of entrance to Ethiopia, Massawa, was at the time controlled by the Ottoman Empire, which was hostile to both Ethiopian and European interests. The party crossed the desert into the Ethiopian highlands, and reached Fremona, the base of Catholic missionary efforts, on 21 June 1625, over two years after Mendes had left Lisbon.
At a public ceremony on 11 February 1626, the Emperor Susenyos and Patriarch Mendes publicly acknowledged the primacy of the Roman See and made Catholicism the state religion. A number of local practices were condemned, which included Saturday Sabbath and frequent fasts. For a time, conversions were made, the monarch frequently resorting to compulsion. Richard Pankhurst reports 100,000 inhabitants of Dembiya and Wegera alone are said to have converted to Catholicism. However, strife and rebellions over the enforced changes began within days of the public ceremony, and at one point the Emperor's son, Fasilides, sided with the native church.
After many years of chronic civil war, on 14 June 1632, Emperor Susenyos issued a formal declaration that those who would follow the Catholic faith were allowed to do so, but no one would be forced to do so any further. Patriarch Mendes could only confirm that this was, indeed, the actual will of the Emperor, his protector. Upon succeeding his father, Fasilides first confined the Catholic hierarchy to Fremona, then in 1634 exiled the Patriarch and several of the foreign priests from Ethiopia, who were exposed to robbery, assaults and other indignities by the local population before reaching the Ottoman Naib at Massawa. The Naib sent them to his superior at Suakin, where the Pasha forced the party to pay a ransom before they could proceed to India. Despite settling for a ransom of 4300 patacas (which he borrowed from local Banyan merchants), at the last moment the Pasha insisted on keeping Patriarch Mendes, two priests, three cleric and two of his servants. Amongst those who departed Suakin on 26 August was Jerónimo Lobo. These were kept prisoner until Mendes managed to raise 4000 pieces of eight as their ransom, and the Pasha put them on a ship bound for Diu on 24 April 1635. They reached Diu a month later, and Mendes immediately continued on to Goa, where he unsuccessfully sought military support for his restoration. He appears to have spent the rest of his life in Goa, where he wrote his book on Ethiopian history and geography and the Jesuit mission in Ethiopia, Expeditionis Aethiopicae. His letters and annual reports in Latin appear in other volumes of the series Rerum Aethiopicarum Scriptores Occidentales.