Nóbrega arrived in the captaincy of Bahia on March 29, 1549, accompanied by five other Jesuits. The Governor-General's first act was to found the colonial capital city of Salvador (The Savior, in Portuguese) and to celebrate its first mass on 1549.
Nóbrega and his colleagues tried to fulfill their mission but faced many difficulties because the colonists mistreated and tried to enslave the Indians. He soon was fiercely engaged in the defense of the Indians, a posture which lead to serious clashes with inhabitants and authorities of the new colony, alike, including the first Governor-General and the one who succeeded him, Duarte da Costa.
To gain authority in his fight against the colonists, Nóbrega asked the King to establish an episcopacy in Brazil, which was granted on February 25, 1551. The first Bishop of Brazil, Dom Pedro Fernandes Sardinha took office on June 22 1552, By then, Nóbrega, an efficient entrepreneur, had already created the Jesuit College of Salvador. Nóbrega was then nominated the first Provincial of the Society of Jesus in the New World, a post which he held until 1559. Unfortunately, Dom Sardinha was killed and eaten by hostile Indians after a shipwreck, changing Nóbrega's mind in relation to the Indian mission.
Sensing the difficulties of converting adult Indians to Christianity, Nóbrega determined that the Jesuit's efforts should concentrate on the teaching of children, which were more pliable, and the Jesuits started to create elementary schools for teaching Portuguese and Latin, basic literacy and religion. The Jesuits discovered that singing was a very effective way of winning the attention of the students, and so Nóbrega was one of the pioneers in using music in education. To help in the evangelization of children, Nóbrega had the idea of bringing in 1550 seven orphan children to Brazil and making them learn Tupi, the language of the Indians, so that they would be bilingual and act as translators. These children would often go with the Jesuits on foot to faraway places and were protected and cherished by the Indians. Several of the children became Jesuit priests, too.
In 1552, Nóbrega accompanied again Tomé de Sousa to the captaincy of São Vicente, in the present-day Southern state of São Paulo. There, he was joined by another group of Jesuits, who had arrived with José de Anchieta, then a young novice, who travelled with Mem de Sá, the third Governor-General sent by the Crown. Nóbrega determined as the new mission of this small band of missionaries to found villages (aldeamentos) on the high plateau just above the coastline, in order to better pursue their work of catechesis and education of the Indians. Thus, on January 25, 1554, Nóbrega and Anchieta celebrated the first mass in the new and modest Jesuit College of São Paulo dos Campos de Piratininga, in honor of Saint Paul's day of conversion to Christianity. The tiny settlement around this Jesuit school was to become one of the largest metropoles of the world, São Paulo.
The arrival of a French invasion force in 1555, in the Guanabara Bay, Rio de Janeiro (the so-called France Antarctique episode), however, tipped the balance again, since the Indians saw an opportunity to rally the Frenchmen's help to vanquish the hated Portuguese. Thus, Nóbrega had no alternative other than bless and support the punitive expeditions sent by the third Governor-General, Mem de Sá, in 1560 and by his nephew, Estácio de Sá, in 1565. The French colonists were defeated and definitely expelled and their Indian allies were reduced to submission.
After the expulsion of the French invaders, Father Manuel da Nóbrega stayed in Rio and founded a new Jesuit College in the city, the College of Saint Vincent, and was nominated its Rector (Dean). In 1570 he was again nominated Brazilian Provincial of the Jesuit Order, but he died before taking office, on October 18, 1570, the very day he was completing 53 years of age. Seven years later, the Jesuit Provincialship of Brazil was accepted by Anchieta, his great pupil and friend.