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Godlee was born at Upton, Essex to a Quaker family, the second son of Rickman Godlee (1804–1871), a barrister at Middle Temple, and Mary Godlee (née Lister), daughter of Joseph Jackson Lister. He was thus a nephew of Joseph Lister — whose biography he later wrote.

He was educated at a school in Tottenham and took his B.A. at the University College, London before he began his medical education.

An expert draughtsman, and whilst still at the University College, London, he was employed to make the original plates for Quain's Anatomy — which in 1920 he presented to the Royal College of Surgeons of England.

He was admitted a Member of the Royal College of Surgeons in 1872, and four years later was elected to the fellowship — having in the meantime won gold medal at both his Bachelor and Master of Surgery examinations at the University of London.

After a periods as house surgeon then house physician at University College Hospital, London, he moved to Edinburgh to practise the new surgical techniques being developed there by his uncle, Joseph Lister. On his return to London he was appointed assistant surgeon at Charing Cross Hospital, and to a similar position at the North Eastern Hospital for Children. After a period as assistant surgeon at University College Hospital, he became surgeon at Brompton Hospital, London, where he made advances in surgery of the chest.

At the Epileptic Hospital, Regent's Park in 1884 he became one of the first to remove a tumour of the brain surgically.

In 1885 he was appointed surgeon at University College Hospital, and Emeritus Professor of Clinical Surgery there in 1892. He was President of the Royal College of Surgeons in 1911, 1912 and 1913. He was Surgeon to the Household of Queen Victoria and Surgeon Ordinary to Edward VII and to George V.

He was created a baronet in 1912 and gazetted KCVO in 1914.