Isabella's father was the regent for her cousin Afonso V during his minority. Reportedly, Isabella and Afonso fell in love with each other. They were engaged in 1445, which caused a conflict between Peter of Coimbra and Duke Afonso of Braganza, who had wished for the monarch to marry his grandchild. Isabella was given the income of Santarém, Alvaiázere, Sintra and Torres Vedras at her wedding.
In 1448, the king took Afonso of Braganza as his advisor. Isabella's father died (suspected to have been killed), and her brother John was exiled. Isabella herself did not fall out of favour with the king, however, and she took control of the duchy of Coimbra until her brother returned to Portugal in 1454. In 1455, Isabella had her father honoured with a grand ceremony of exoneration at court and had him re-buried in a grand way. Shortly after this, she died at age twenty-three, possibly from poisoning.