The eminent surgeon lived in Prudhoe Street. He opened a Hospital for Diseases of the Eye in Brunswick Place in 1822 and over the next nine years, 7,000 patients were treated. This institution moved to Prudhoe Street and later to Saville Row. In 1832 Fife and Thomas Headlam helped to found the Newcastle School of Medicine and Surgery.
Fife was a prominent Reform Bill agitator (called an 'idol of the mob') and spoke at the great meeting on Cow Hill, with 50,000 present on 17 October 1831. Thomas Hepburn (q.v.) was also on the platform. On 25 October Fife was among the 300, mostly ironworkers from Winlaton, who marched to prevent intimidation of a meeting in Durham. The Marquis of Londonderry had threatened to break up the gathering with the Durham Yeomanry - his 'lambs' as he called them. After becoming members of the first reformed council, Headlam and Fife turned on their former radical allies. Fife was mayor of Newcastle in 1838-9 and again in 1843. He was knighted in 1840 for suppressing a Chartist outbreak the previous year. It was noticed that when Fife returned from London by ship, his baggage was conspicuously labelled 'Sir John Fife, Newcastle upon Tyne'.

Fife, with the assistance of Robert Glover (q.v.) carried out the autopsy on fifteen-year-old Hannah Greener of Winlaton, who had died under anaesthetic. She is regarded as the first victim of chloroform anaesthesia.