At the age of thirteen, he was sent to the university of Edinburgh. Here he also distinguished himself by the superiority of his talents, and in particular by the progress he made in classical acquirements, and in the study of theology. He had the good fortune, likewise, while attending college to form intimacies with some of the most celebrated men of the last century. Amongst these were Dr Robertson, David Hume, Adam Smith and John Home. Mr Mackenzie, in his life of the last mentioned individual, says that Wilkie’s friends all spoke of him as "superior in genius to any man of his time, but rough and unpolished in his manners, and still less accommodating to the decorum of society in the ordinary habits of his life. Charles Townsend, a very competent judge of men," continues the biographer, "and who, both as a politician and a man of the world was fond of judging them, said, after being introduced to Wilkie, and spending a day with him at Dr Carlyle’s, that he had never met with a man who approached so near to the two extremes of a god and a brute as Dr Wilkie."

While prosecuting his studies at Edinburgh, Wilkie lost his father who died in straitened circumstances, but left his son the stock and unexpired lease of a farm at Fishers’ Tryste, a few miles south of the city, burdened however, with the charge of maintaining his three sisters who were otherwise wholly unprovided for; Wilkie, in consequence of this event, became a farmer, but, unwilling to trust entirely to that profession for his future subsistence, he continued, while conducting the business of his farm, to prosecute his studies in divinity and eventually was licensed as a preacher of the gospel although some years elapsed before he obtained a church. Previously to his assumption of the gown, he had made himself an export farmer, and so remarkable was he, in particular, for his successful culture of the potatoe, then but indifferently understood, that he obtained the facetious by-name of the potatoe minister. But, while he claimed and really possessed the merit of being a superior agriculturist to any of his neighbours, he always acknowledged that he was their inferior in the art of trafficking, and the manner in which he made this boast and acknowledged this inferiority was characteristic of the man; "I can raise crops," he would say, "better than any of my neighbours, but I am always cheated in the market."

While pursuing his farming occupations at Fishers’ Tryste, which he did with the most laudable industry and perseverance, labouring much and frequently with his own hands, he did not neglect those studies which his classical education had placed within his reach. It was here and while labouring with scythe and sickle, ploughing and harrowing, that he conceived, and at intervals of leisure, in part wrote his poem of "The Epigoniad," the work which acquired him what celebrity he possesses.

Through the influence of Mr Lind, sheriff-substitute of Mid Lothian, who resided in his neighbourhood, and who knew of and appreciated his abilities, Mr Wilkie obtained the appointment of assistant and successor to Mr Guthrie, minister of Ratho. To this office he was ordained by the presbytery on the 17th May, 1753. Three years afterwards, during all which time he continued to reside on and cultivate his farm, he succeeded to the entire living by the death of the incumbent.

In 1757, Mr Wilkie published at Edinburgh "The Epigoniad, a Poem in Nine Books," 12mo, and in 1759, a second edition, corrected and improved, with the addition of "A Dream, in the manner of Spenser." The Epigoniad obtained a temporary and local celebrity of no unenviable kind. It was read and admired by the learned of Scotland, and has been so frequently alluded to in contemporary literature, that even yet, when perhaps there is hardly a living man who has read it, nothing like oblivion can be said to have overtaken it. Mackenzie, in his life of Home, speaks of it as "a poem of great merit, not only as possessing much of the spirit and manner of Homer, but also a manly and vigorous style of poetry, rarely found in modern compositions of the kind." The same critic, after remarking the want of feeling which characterized Wilkie, goes on to say, "Perhaps it is to a want of this poetical sensibility that we may chiefly impute the inferior degree of interest excited by Wilkie’s Epigoniad, to that which its merits in other respects might excite. Perhaps it suffers also from its author having the Homeric imitation constantly in view, in which, however, he must be allowed, I think, to have been very successful,—so successful that a person ignorant of Greek, will, I believe, better conceive what Homer is in the original by perusing the Epigoniad, than by reading even the excellent translation of Pope."

After his establishment at Ratho, Mr Wilkie became a frequent and welcome visitor at Hatton, the residence of the earl of Lauderdale, the patron of the parish, who highly esteemed him for his worth and talents, and was particularly fond of his society.

In 1750, he became a candidate for the chair of natural philosophy in the university of St Andrews, then vacant by the death of Mr David Young, and was successful. After settling in St Andrews, the poet purchased some acres of land, and resumed his farming occupations, in which he succeeded so well as to leave at his death property to the amount of £3000. Sometime after his appointment to the professorship, the university conferred on him, as a mark of its sense of his merits, the degree of doctor in divinity.

In 1768, Dr Wilkie published a series of sixteen "Moral Fables, in Verse," 8vo; but these, though sufficiently ingenious productions, did not advance him, much farther in public favour as a poet. With this circumstance the remarkable occurrences of his life terminate. After a lingering indisposition, he died at St Andrews, on the 10th October, 1772, in the fifty-first year of his age.

Of Dr Wilkie’s personal peculiarities some curious anecdotes have been preserved. Amongst the most amusing and extraordinary of his eccentricities was a practice of sleeping with an immoderate quantity of bed-clothes, and a detestation which he entertained of clean sheets. He has been known to sleep with no less than four and twenty pair of blankets on him; and his abhorrence of clean sheets was so great, that, whenever he met with them in any bed in which he was to lie, he immediately pulled them off crumpled them together, and threw them aside. On one occasion, being pressed by lady Lauderdale to stay all night at Hatton, he agreed, though with reluctance, and only on condition that her ladyship would indulge him in the luxury of a pair of foul sheets!