He was born in Sintra, the eldest son of King Edward of Portugal by his wife, Infanta Eleanor of Aragon. Afonso V was only six years old when he succeeded his father in 1438.

During his minority, Afonso V was placed under the regency of his mother, according to a late will of his father. As both a foreigner and a woman, the queen was not a popular choice for regent. Opposition rose and the queen's only ally was Afonso, Count of Barcelos, the illegitimate half brother of King Edward and count of Barcelos. In the following year, the Cortes (assembly of the kingdom) decided to replace the queen with Infante Peter, Duke of Coimbra, the young king's oldest uncle. His main policies were concerned with avoiding the development of great noble houses, kingdoms inside the kingdom, and concentrating power in the person of the king. The country prospered under his rule, but not peacefully, as his laws interfered with the ambition of powerful nobles. The count of Barcelos, a personal enemy of the Duke of Coimbra (despite being half - brothers) eventually became the king's favourite uncle and began a constant struggle for power. In 1442, the king made Afonso the first Duke of Braganza. With this title and its lands, he became the most powerful man in Portugal and one of the richest men in Europe. To secure his position as regent, in 1445 Peter had Afonso marry his daughter, Isabella of Coimbra.

But in 9 June 1448, when the king came of age, Peter had to surrender his power to Afonso V. The years of conspiracy by the Duke of Braganza finally came to a head. On 15 September of the same year, Afonso V nullified all the laws and edicts approved under the regency. The situation became unstable and, in the following year, being led by what he afterwards discovered to be false representations, Afonso declared Peter a rebel and defeated his army in the Battle of Alfarrobeira, in which his uncle (and father - in - law) Peter was killed. After this battle and the loss of one of Portugal's most remarkable infantes, the Duke of Braganza became the de facto ruler of the country.

Afonso V then turned his attentions to the North of Africa. In his grandfather's reign, Ceuta had been conquered by the king of Morocco, now the new king wanted to expand the conquests. The king's army conquered Alcácer Ceguer (1458), Tangiers (won and lost several times between 1460 and 1464) and Arzila (1471). These achievements granted the king the nickname of the African. The king also supported the exploration of the Atlantic Ocean led by prince Henry the Navigator but, after Henry's death in 1460 he did nothing to pursue this course of action. Administratively, Afonso V was an absent king, since he did not pursue development of laws or commerce, preferring to stand with the legacy of his father and grandfather.

In 1452, Pope Nicholas V issued the papal bull Dum Diversas, granting Afonso V the right to reduce any "Saracens, pagans and any other unbelievers" to hereditary slavery. This approval of slavery was reaffirmed and extended in the Romanus Pontifex bull of 1455 (also by Nicholas V). These papal bulls came to serve as a justification for the subsequent era of slave trade and European colonialism.

When the campaigns in Africa were over, Afonso V found new grounds for battle in the Iberian Peninsula. In neighbouring Castile, a huge scandal with political and dynastic implications had arisen. King Henry IV of Castile died without a male heir. From his two marriages, only a daughter, Joan of Castile, had been born. But her paternity was questioned, as rumour said the king was impotent and the queen, Joan of Portugal, had a notorious affair with a nobleman called Beltrán de La Cueva. The birth of princess Joan in 1462, openly called the Beltraneja, caused the separation of her parents. She was never considered legitimate and, when the king was dying, no one took her as a serious contender for the crown. Her half - aunt, the future Queen Isabella I of Castile, was due to inherit the crown, but Afonso V was keen to interfere with the succession in Castile. In 1475 he married his niece Joan, the Beltraneja, whom he considered the legitimate heir to the crown. Since her adulteress mother was his own sister, Afonso V had not only ambition, but the family honour to protect. He proclaimed himself King of Castile and León and prepared to defend his wife's rights. In the following year he was defeated at the Battle of Toro by King Ferdinand V of Castile, the husband of Isabella I of Castile. He went to France to obtain the assistance of Louis XI, but finding himself deceived by the French monarch, he returned to Portugal in 1477 in very low spirits. Disillusioned and depressed, he fell into a deep melancholy and abdicated in favour of his son, John II. After this, he retired to a monastery in Sintra where he died in 1481. His death was mourned in the country, by the people who loved the king, and by the nobles who were starting to fear his successor.

Afonso married first to his cousin Isabella of Coimbra in 1447. Isabella died in 1455 and Afonso married again (although not recognized by the Papacy) in 1475, this time to Joan of Castile (known as "la Beltraneja"), daughter of Henry IV of Castile and Joan of Portugal. This marriage was an attempt to inherit the throne of Castile as Joan was the sole daughter of Henry IV. However this did not happen as Afonso lost a short war with Castile.