Educated at Wolverhampton Grammar School, he was apprenticed in 1779 to Sir Charles Blicke (1745–1815), a surgeon at St Bartholomew's Hospital, London.

[5] Abernethy's Surgical Observations on the Constitutional Origin and Treatment of Local Diseases (1809) – known as "My Book",[6] from the great frequency with which he referred his patients to it, and to page 72 of it in particular, under that name – was one of the earliest popular works on medical science.

He taught that local diseases were frequently the results of disordered states of the digestive organs, and were to be treated by purging and attention to diet.

It has been said however, that the influence he exerted on those who attended his lectures was not beneficial in this respect, that his opinions were delivered so dogmatically, and all who differed from him were disparaged and denounced so contemptuously, as to repress instead of stimulating inquiry.

[9] Abernethy believed that a variety of diseases originated in a disordered state of the digestive organs, and that treating underlying maldigestion and dyspepsia was essential to restoring health.

[14] His debate with Sir William Lawrence is believed by Marilyn Butler to have influenced Mary Shelley's Frankenstein.