His education was of the plainest kind, but he was eager for culture, fond of reading, and anxious to become an artist. His father, however, placed him, in 1820, in Newenham's Bank, where he remained for two years, and then left to study in the Cork school of art. In 1825 it happened that Sir Walter Scott was travelling in Ireland, and young Maclise, having seen him in a bookseller's shop, made a surreptitious sketch of the great man, which he afterwards lithographed. It was exceedingly popular, and the artist became celebrated enough to receive many commissions for portraits, which he executed, in pencil, with very careful treatment of detail and accessory.

Various influential friends perceived the genius and promise of the lad, and were anxious to furnish him with the means of studying in the metropolis; but with rare independence he refused all aid, and by careful economy saved a sufficient sum to enable him to leave for London. There he made a lucky hit by a sketch of the younger Kean, which, like his portrait of Scott, was lithographed and published. He entered the Academy schools in 1828, and carried off the highest prizes open to the students.

In 1829 he exhibited for the first time in the Royal Academy. Gradually he began to confine himself more exclusively to subject and historical pictures, varied occasionally by portraits of Campbell, Miss Landon, Dickens, and other of his literary friends. In 1833 he exhibited two pictures which greatly increased his reputation, and in 1835 the Chivalric Vow of the Ladies and the Peacock procured his election as associate of the Academy, of which he became full member in 1840. The years that followed were occupied with a long series of figure pictures, deriving their subjects from history and tradition and from the works of Shakespeare, Goldsmith and Le Sage.

The intense application which he gave to these great historic works, and various circumstances connected with the commission, had a serious effect on the artist's health. He began to shun the company in which he formerly delighted; his old buoyancy of spirits was gone; and when, in 1865, the presidentship of the Royal Academy was offered to him he declined the honor. He died of acute pneumonia on the 25th of April 1870.