Full of energy and hope, he left home, on 14 May 1804, for London, and entered the Royal Academy as a student. He was so enthusiastic that Henry Fuseli asked when he ever found time to eat. Aged twenty-one (1807) Haydon exhibited, for the first time, at the Royal Academy, The Repose in Egypt, which was bought by Thomas Hope the year after for the Egyptian Room at his townhouse in Duchess Street. This was a good start for the young artist, who shortly received a commission from Lord Mulgrave and an introduction to Sir George Beaumont. In 1809 he finished his well-known picture of Dentatus, which, though it increased his fame, resulted in a lifelong quarrel with the Royal Academy, whose committee had hung it in a small side-room instead of the great hall. That same year, he took on his first pupil, Charles Lock Eastlake, later destined to become one of the great figures of the British art establishment.

In 1810 his financial difficulties began when the allowance of £200 a year from his father was stopped. His disappointment was embittered by the controversies in which he now became involved with Beaumont, for whom he had painted his picture of Macbeth, and Richard Payne Knight, who had denied the beauties as well as the money value of the Elgin Marbles. The Judgment of Solomon, his next production, gained him £700, besides £100 voted to him by the directors of the British Institution, and the freedom of the borough of Plymouth. To restore his health and escape for a time from the cares of London life, Haydon joined his intimate friend David Wilkie in a trip to Paris; he studied at the Louvre; and on returning to England, produced Christ's Entry into Jerusalem, which afterwards formed the nucleus of the American Gallery of Painting, erected by his cousin, John Haviland of Philadelphia. Whilst painting another large work, the Resurrection of Lazarus, his financial problems increased, and he was arrested but not imprisoned, the sheriff officer taking his word for his appearance. Yet in October, 1821, he married a beautiful young widow with children, Mrs. Hyman, to whom he was devoted.

In 1823 Haydon was imprisoned in the King's Bench Prison, where he received consoling letters from leading men of the day. While there, he drew up a petition to Parliament in favour of the appointment of "a committee to inquire into the state of encouragement of historical painting," which was presented by Lord Brougham. During a second imprisonment in 1827, he produced the picture of the Mock Election, the idea of which had been suggested by an incident in the prison. King George IV gave him £500 for this work. Among Haydon's other pictures were: Eucles and Punch (1829); Napoleon at St Helena, for Sir Robert Peel; Xenophon, on his Retreat with the 'Ten Thousand,' first seeing the Sea; and Waiting for the Times, purchased by the Marquis of Stafford (all 1831); and Falstaff and Achilles playing the Lyre (1832). In 1834 he completed the Reform Banquet, for Lord Grey — this painting contained 597 portraits; in 1843, Curtius Leaping into the Gulf, and Uriel and Satan. There was also the Meeting of the Anti-Slavery Society, energetically treated, now in the National Portrait Gallery.

When the competition took place at Westminster Hall, Haydon sent two cartoons, The Curse of Adam and Edward the Black Prince, but he was not given a prize for either. He then painted The Banishment of Aristides, which was exhibited with other productions under the same roof where the American dwarf General Tom Thumb was making his debut in London. The exhibition was unsuccessful; and the artist's difficulties increased to such an extent that, whilst employed on his last grand effort, Alfred and the Trial by Jury, overcome by debts of over £3000.0, disappointment and ingratitude, he wrote "Stretch me no longer on this rough world," and committed suicide by shooting himself, at sixty-one years of age. The bullet failed to kill him; he finished the task by slitting his throat. He left a widow and three surviving children, who were rescued from poverty by the generosity of their father's friends; amongst the foremost of these friends were Sir Robert Peel, Count d'Orsay, Mr. Justice Talfourd, and Lord Carlisle.

Haydon was well known as a lecturer on painting and design, and from 1835 onwards visited all the principal towns in England and Scotland on lecture tours. His ambition was to see the chief buildings of Britain adorned with history paintings representing her glory. He lived to see the establishment of schools of design, and the embellishment of the new Houses of Parliament; but in the competition of artists for the carrying out of this object, the commissioners (including one of his former pupils) considered that he had failed. Haydon's Lectures, which were published shortly after their delivery, showed that he was as bold a writer as painter. It may be mentioned in this connection that he was the author of the long and elaborate article, "Painting," in the 7th edition of the Encyclopædia Britannica.

Haydon wrote an autobiography, which was assessed by the Encyclopædia Britannica Eleventh Edition this way:

Haydon's autobiography is one of the most natural books ever written, full of various and abundant power, and fascinating to the reader. His love for his art was both a passion and a principle. He found patrons difficult to manage; and did not have the tact to lead them gently. He failed, abused patrons and patronage, and intermingled talk of the noblest independence with acts not always dignified. He was self-willed to perversity, but his perseverance was such as is seldom associated with so much vehemence and passion. He had confidence in his own powers and in the ultimate triumph of art. He proclaimed himself the apostle and martyr of high art, and believed himself to have a claim on the sympathy and support of the nation.

Readers of his autobiography were struck by the frequency and fervour of the short prayers interspersed throughout the work. Haydon had an overwhelming sense of a personal, overruling and merciful providence, which influenced his relations with his family, and to some extent with the world. He had many enemies, actuated by motives as unworthy as his own were always high-pitched and on abstract grounds laudable.

Charles Dickens wrote in 1846 that "All his life [Haydon] had utterly mistaken his vocation. No amount of sympathy with him and sorrow for him in his manly pursuit of a wrong idea for so many years — until, by dint of his perseverance and courage it almost began to seem a right one — ought to prevent one from saying that he most unquestionably was a very bad painter, and that his pictures could not be expected to sell or to succeed."

Again according to the Encyclopædia Britannica Eleventh Edition, "Of his three great works — Solomon, Entry into Jerusalem and Lazarus — the second is generally regarded as the finest. Solomon shows his executive power at its loftiest, and is of itself enough to place Haydon at the head of British historical painting in his own time. Lazarus is a more unequal performance, and in various respects open to criticism; yet the head of Lazarus is so majestic and impressive that, if its author had done nothing else, we must still pronounce him a potent pictorial genius."