Historians believe he was born in Veiros, Estremoz, Alentejo, as a natural son of Portuguese King John I and Inês Peres. He married the heiress Beatriz Pereira de Alvim, daughter of Nuno Álvares Pereira, a general and the wealthiest man in the kingdom.
A traveled and cultivated man, Afonso was present in 1415 when the Portuguese conquered Ceuta. When his half-brother King Edward I of Portugal died in 1438, his son Afonso V (Afonso's nephew) was an infant and the choice for the regency was his sister-in-law, the Queen Mother Eleonor of Aragon.
This choice for the regency was not popular because Eleonor was Aragonese, so in a meeting of the Portuguese Cortes summoned by Afonso's half-brother John, Lord of Reguengos de Monsaraz, the regency was awarded to the Infante Peter, Duke of Coimbra, another half-brother of Afonso and an uncle of the young king. This choice pleased both the people and the fast-growing bourgeoisie.
Within the Portuguese aristocracy, however, especially those in the circle around Afonso, Eleonor of Aragon was preferred, and there were doubts about Peter's political policies. A contest for the young king's affection began, and within a few years, Afonso managed to become Afonso V's favourite uncle.
In 1443, in a gesture of reconciliation, Peter made Afonso the first Duke of Braganza. But, in 1445, Afonso took offence because Isabella of Coimbra, Peter's daughter, became the choice for Afonso V's wife, and not one of his granddaughters. Indifferent to the intrigues, Peter continued his regency and the country prospered under his rule. It was during this period that the first subsidies for the exploration of the Atlantic Ocean were appropriated under the supervision of Henry the Navigator (another of Afonso's half-brothers).
On 9 June 1448, King Afonso V came of age, and Peter turned over control of the country to the king. An ambitious man, he persuaded the young king to turn against Peter. Influenced by Afonso, the king nullified all of Peter's edicts. The following year, under accusations that years later would prove false, Afonso V declared his uncle Peter a rebel. The situation became unsustainable and a civil war begun. On 20 May 1449, during the Battle of Alfarrobeira, near Alverca, Peter was killed.
After the Battle of Alfarrobeira, Afonso V gave new powers to his uncle Afonso and nine years later when he departed to Africa, the regency was delegated to him.
Afonso married twice. His first marriage was to Beatriz Pereira de Alvim, on 8 November 1401, with whom he had three children:
Afonso married a second time, to his third cousin, Constance of Noronha, daughter of Alfonso Enríquez, Count of Gijón and Noreña (a natural son of Henry II of Castile), and of Isabel of Portugal (a natural daughter of Fernando I of Portugal). They had no issue.