Henry was born in Dudley, West Midlands, the son of parents who migrated to Britain from Jamaica in the 1950s.

He studied at Bluecoat Secondary Modern School, WR Tewson School, and Preston College, and has since obtained a degree in English literature from the Open University.

His earliest TV appearance was on the New Faces TV talent show in 1975 where he was a repeat winner. His formative years were in working men's clubs where his unique act - a young black man impersonating white characters such as Frank Spencer (whom he impersonated on New Faces) gave him an edge in what were racially divisive times. He also toured for five years as a comic performer with The Black and White Minstrel Show, the only black performer in a troupe where the men all appeared in blackface.

He co-hosted the children's programme Tiswas from 1978 until 1980, and subsequently performed and wrote for the show Three of a Kind with comedians Tracey Ullman and David Copperfield. Around this time he met his future wife, Dawn French, who encouraged him to move over to the fledgling alternative comedy scene, where he established a career as a stand-up comedy performer and character comedian. He introduced characters which both mocked and celebrated black British culture, such as Theophilus P. Wildebeeste (a Barry White-a-like), Brixton pirate radio DJ Delbert Wilkins and Trevor MacDoughnut (a spoof on Trevor McDonald). Much of his stand-up material, which was enormously popular on recorded LP, owed much to the writing abilities of Kim Fuller.

Henry's TV work started principally with his own self-titled show, which has appeared in variant forms ever since. He was also a part-time member of The Comic Strip.

In the early 1990s, Henry was lured to Hollywood to star in the film True Identity, in which his character spent most of the film pretending to be a white person (using make-up, prostheses, and a wig) in order to avoid the mob.

The film, though excellent, was not commercially successful, and it has been suggested that part of the problem was that the film's producers (Disney) didn't really understand Henry and used him in a project that wasn't suited to his talents. However in 1991 he starred in a BBC drama along side Robbie Coltrane called Alive and Kicking where he plays a heroin addict.

Henry is perhaps best known to modern audiences as the choleric chef of the comedic 1990s television series Chef!, or from his 1999 straight-acting lead role in the BBC drama Hope And Glory.

Henry tried his hand at soul singing, appearing, for example, as a back-up singer on Kate Bush's album The Red Shoes (1993) and, backed by David Gilmour of Pink Floyd at Amnesty International's Big 3-0 fund raising concert. He would later say that both moves were not showing him at his best and that he felt most comfortable with character comedy, returning to the BBC to do Lenny Henry in Pieces, a character-based comedy sketch show. He followed this with The Lenny Henry Show in which he combined stand-up, character sketches and song parodies.

In 2003, he was listed in The Observer as one of the 50 funniest acts in British comedy.

He married comedy actress Dawn French on 20 October 1984. They have an adopted daughter, Billie.

Henry is also one of the celebrities most associated with the British Comic Relief charity organisation along with Griff Rhys Jones, and has hosted the show as well as presented filmed reports from overseas on the work of the charity.

He lent his voice to the "shrunken head" on the Knight Bus in the 2004 movie Harry Potter and the Prisoner of Azkaban and read the audio book version of Neil Gaiman's "Anansi Boys".