He studied art in Paris, and moved to Antwerp, Belgium, where he lost vision in his left eye. He consulted an oculist in Düsseldorf, Germany, where he met his future wife, Emma Wightwick. He followed her family to London, where he married Emma in 1863.

He became a member of the staff of the satirical magazine Punch in 1865, drawing two cartoons a week. His most common targets were the affected manners of Victorian society. His most enduringly famous cartoon, 'True Humility', was the origin of the expressions 'good in parts' and 'a curate's egg'. (In the caption, a bishop addresses a curate [a very humble class of clergyman] whom he has condescended to invite to breakfast: 'I'm afraid you've got a bad egg, Mr. Jones.' The curate replies, 'Oh no, my Lord, I assure you — parts of it are excellent!') In an earlier (1884) cartoon, du Maurier had coined the expression 'bedside manner', which he satirized in contrast to actual medical skill. Another of du Maurier's notable cartoons was of a videophone conversation in 1879, using a device he called 'Edison's telephonoscope'.

Owing to his deteriorating eyesight, du Maurier reduced his involvement with Punch in 1891 and settled in Hampstead, where he wrote three novels. His first, Peter Ibbetson, was a modest success at the time and later adapted to stage and screen, most notably in the 1935 film starring Gary Cooper, and as an opera.

His second novel Trilby, was published in 1894. It fit into the gothic horror genre which was undergoing a revival during the fin de siecle, and the book was very popular. The story of the poor artist's model Trilby O'Ferrall, transformed into a diva under the spell of the evil musical genius Svengali, created a sensation. Soap, songs, dances, toothpaste, and even a city in Florida were all named for the heroine, and the variety of soft felt hat with an indented crown that was worn in the London stage dramatization of the novel, is known to this day as a trilby. The plot inspired Gaston Leroux's 1910 novel Phantom of the Opera and the innumerable works derived from it. Although initially bemused by Trilby's success, du Maurier eventually came to despise the persistent attention given to his novel.

The third novel was a long, largely autobiographical work entitled The Martian, which was only published posthumously.

George du Maurier was a close friend of Henry James, the novelist; their relationship was fictionalised in David Lodge's Author, Author.

He was interred in Saint John's Churchyard in Hampstead parish in London.