To escape from an outbreak of bubonic plague in 1530 Barros moved from Lisbon to his country house near Pombal, where he finished a moral dialogue, Rho pica Pneuma, which was praised by Juan Luís Vives.

Barros proved a good administrator, displaying great industry and an honesty rare at the time, with the result that he made little profit compared to his predecessors, who had amassed fortunes.

He formed a partnership with two merchants, Aries da Cunha and Alvares de Andrade, and sent an expedition consisting of ten vessels and 900 men to Brazil.

During these years he had continued his studies in his leisure hours, and shortly after the Brazilian disaster he offered to write a history of the Portuguese in India, the Décadas da Ásia, which the king accepted.

His 1543 text Diálogo evangélico sobre os artigos da fé contra o Talmud dos Judeus makes anti-Jewish remarks.

In January 1568 Barros retired from his remunerative appointment at the India House, receiving the rank of fidalgo together with a pension and other pecuniary emoluments from King Sebastian, and died on 20 October 1570.