Born in Lisbon, Rego was sent to finishing school in Sevenoaks in England. She left to the Slade School of Art where she met the artist Victor Willing, whom she eventually married. The two divided their time between Portugal and England until 1975, when they moved to England. Willing later died after suffering for some years from multiple sclerosis.
Rego has stated that illustrative art (such as that in the Beatrix Potter books) and fairy tales were important early influences. Her work sometimes includes imagery from fairy tales with a sinister edge. Early pieces sometimes use collaged elements taken from Rego's own drawings, with later works often being in vinyl paint on paper.
Rego's style is often compared to cartoon illustration. As in cartoons, animals are often depicted in human roles and situations. Later work adopts a more realistic style, but sometimes keeps the animal references - the Dog Woman series of the 1990s, for example, is a set of pastel pictures depicting women in a variety of dog-like poses (on all fours, baying at the moon, and so on).
Rego has also painted a portrait of Germaine Greer, which is in the National Portrait Gallery in London.
Rego was shortlisted for the Turner Prize in 1989.