He resigned his Fellowship in 1750, as he was required to do on his marriage, and he and his wife took up residence at Dunston, Lincolnshire, where he looked after the local interests of Sir Francis Dashwood whilst apparently practising medicine.

Although Willis was ordained in accordance with his father's wishes, his chief interest was in medicine and he received the degrees of Bachelor and Doctor of Medicine from Oxford in 1759 before serving as a hospital physician in Lincoln, where his early successes with the mentally ill, or "wrongheads" as they were commonly known at the time, led to him treating such patients in his own home:It is said that the great success that attended the eminent Dr Willis had its origin in an experiment tried upon a tradesman of Lincoln, who on becoming insane was taken to Dunston, where the treatment of his malady was such that in a short time he was enabled to return to this city and resume his duties behind the counter.

As part of the treatments his patients were encouraged to perform manual work in and around the stables and fields of the Greatford estate, the fresh air and exercise likely contributing to their recovery.

On visiting the estate in 1796, Frederick Reynolds recorded:[9] As the unprepared traveller approached the town, he was astonished to find almost all the surrounding ploughmen, gardeners, threshers, thatchers and other labourers attired in black coats, white waistcoats, black silk breaches and stockings, and the head of each "bewigged, well powdered, neat and arranged.These were the doctor's patients with dress, neatness of person, and exercise being a principle feature of his admirable treatment system where health and cheerfulness conjoined to aid recovery of every person attached to that most valuable asylum.Dr Willis married Mary Curtois and their children included Rear Admiral Richard Willis.

George III had his first attack of madness, possibly attributable to porphyria, which could have been triggered by an excess of rich wines, or more likely an over exposure to the arsenic related to the elaborate hats commonly worn in the Georgian period (though this diagnosis has been challenged, with various other causes being put forward, such as bipolar disorder).

[12] The King's recovery made Willis's national reputation and he had to open a second establishment at nearby Shillingthorpe Hall (in the parish of Braceborough) to accommodate the numbers of patients seeking his help.

John Willis of Lincoln A descendant of an ancient family of the same name That resided formerly at Fenny Compton in Warwickshire He studied at Oxford; was Fellow and sometime Vice-Principal of Brazen Nose College: Where in obedience to his father, he entered into holy orders.

Initiated early into habits of observation and research, he attained the highest eminence in his profession and was happily the chief agent in removing the malady which affected his present majesty in the year 1789.

The Willises are portrayed as the callous jailers of Windsor Castle in Susanna Clarke's novel Jonathan Strange & Mr Norrell, under the impression that visitors, exercise, or other distractions would provoke hysteria in King George III.