Under the auspices of this relation Holmes entered the medical department of the British army in 1787, stating that 'as was customary in those days I paid 400 guineas' for a commission.
Both posts were unpaid, but they carried prestige that was valuable in building up a clientele as, no doubt, did his position of Deputy Grand Master of the Lower Canadian Freemasons from 1805.
In 1788, Gray wrote to Michel Cornud of Quebec (father-in-law of Denis-Benjamin Papineau), Our Ward, Mary Anne, has with my consent engaged herself to marry Mr William Holmes, Surgeon to the 5th Regiment, a young man of good character and has something independent of his surgery who I think will be as good a match as ever she could expect to meet with, and if you should be of the same opinion, I request that you will send me a license (by the return of the post), as I am of opinion that the sooner business of this sort is finished the better it will be for the lady, as she seems to be rather capricious occasioned perhaps by some sort of improper attachment... William and Mary Anne were the parents of five surviving children: His second marriage was in 1807, to Margaret MacNider (1764–1838), the widow of Colonel James Johnston (1724-1800).
They had one daughter, Retiring on half pay from the army, Holmes became a keen farmer and owned well-kept properties along Chemin Sainte-Foy and the road to Cap-Rouge.
He attempted to introduce fresh air and exercise and to remove restraint in the treatment of the insane, as advocated by the French specialist and theorist Philippe Pinel, but continued overcrowding in the older cells undermined such care.
The Dictionary of Canadian Biography summarises his career, In his appointive positions Holmes represented the medical establishment and British military and executive authority in a period of professional and political conflict and change.
As the system of health care and the medical profession became increasingly entangled in the political struggle between the assembly and the executive branch in the Lower Canadian legislature, Holmes tended to draw apart.