Leech's work was compared to Robert Seymour, who at the time was working with Charles Dickens. While working on The Pickwick Papers Seymour committed suicide on the 20th April 1836. Leech was short-listed to become Seymour's replacement but the job eventually went to Hablot Knight Browne. As Browne's biographer, Robert L. Patten, has pointed out: "Dickens recommended Browne for the position. Though the author was an exacting taskmaster, Browne supplied everything Dickens needed in an illustrator. He was a skilled and rapid designer, co-operative, witty, and self-effacing."

Although influenced by the work of James Gillray and George Cruikshank, Leech's humour was as one critic pointed out "less grotesque, less boisterous, less exaggerated, nearer to the truth and to ordinary experience." John Ruskin, the most important art critic of the time wrote: "John Leech's work contains the finest definition and natural history of the classes of our society; the kindest and the subtlest analysis of its foibles, the tenderest flattery of its pretty and well-bred ways, with which the modesty of subservient genius ever immortalised or amused careless masters."

1840 Leech was employed by the London Magazine and Bentley's Miscellany to supply illustrations. The following year he was recruited by a new journal, Punch Magazine, founded by Mark Lemon and Henry Mayhew. Leech's humourous drawings were extremely popular and was one of the main reasons the magazine became a great success. Over the next twenty-three years the magazine published 3,000 of Leech's drawings and 600 cartoons. Simon Houfe has argued: "Leech created a dramatis personae of lovable characters who were instantly recognizable to the Victorian public: the sturdy British householder, the henpecked husband, the plain spinster, the intrepid sportsman Mr Briggs, the Brook Green volunteer, and the dandified and time-serving flunkey Jeames."

Leech was a tall, handsome man with fine features, a wave of brown hair, and blue eyes. In May 1842 Leech married Anne Viola Eaton of Knutton, Staffordshire. They had a daughter, Ada, and a son, John George Warrington Leech. Mrs Leech was frequently the model for his drawings of young women. During this period Leech and his wife became close friends with Charles Dickens and his wife Catherine Dickens.

Dickens suggested that Leech should co-illustrate his next book, Martin Chuzzlewit, with Hablot Knight Browne that was to be published in January 1843. This upset Browne, who had always worked on his own. Valerie Browne Lester, the author of Phiz: The Man Who Drew Dickens (2004) has commented: "On listening to Dickens's synopsis of the plot, he would quickly understand that this particular book did not divide itself clearly into two forms of artistic subject matter. As he was gradually growing away from caricature and grotesquerie, he could imagine that he and Leech, illustrating similar material, would inevitably become objects of comparison." Browne pointed out that Leech had a reputation for not always delivering his work promptly.

Dickens wrote to Leech on 5th November, 1842: "I find that there are so many mechanical difficulties, complications, entanglements, and impossibilities, in the way of the project I was revolving in my mind when I wrote to you last, as to render it quite impracticable. I perceive that it could not be satisfactory to you, as giving you no fair opportunity; and that it would, in practice, be irksome and distressing to me. I am therefore compelled to relinquish the idea, and for the present to deny myself the advantage of your valuable assistance."

In October 1843 Charles Dickens decided to produce a short book for Christmas. The book was to be called A Christmas Carol. He later recalled: My purpose was, in a whimsical kind of masque, which the good humour of the season justified, to awaken some loving and forbearing thoughts, never out of season in a Christian land." George Cruikshank, introduced him to Leech, who agreed to do the illustrations for the book. He was asked to produce four coloured etchings on steel.

A significant percentage of Leech's drawings dealt with political issues. Like the editors of the magazine, Lemon and Mayhew, Leech held fairly radical views. Between 1842 and 1845 Leech produced a series of cartoons such as Capital and Labour , Cheap Clothing and the Agricultural Question , which question the morality of the capitalist system. In the cartoon Substance and Shadow (1843), Leech criticised artists for ignoring social issues such as poverty.

Leech sympathized with those arguing for universal suffrage, however, like most liberals, he strongly opposed the arguments put forward by Feargus O'Conner and the Physical Force Chartists. Leech and Mark Lemon joined the 150,000 special constables recruited in April 1848, when the Chartists held their large Kennington Common demonstration. He wrote to a friend: "Mark Lemon and I were special constables on Monday last. You would have laughed to see us on duty, trying the area gates, etc. Mark continually finding excuses for taking a small glass of brandy and water. Policeman's duty is no joke. I had to patrol about from ten at night till one in the morning, and heartily sick of it I was. It was only my loyalty and extreme love of peace and order that made me stand it." The following week a section of the magazine was devoted to the Chartist rally. One drawing, showing a special constable who cannot remember if he supports or opposes the Chartists, probably reflects Leech's own views.

Leech worked extensively for Punch Magazine, Once a Week and for the Illustrated London News. John R. Harvey, the author of Victorian Novelists and their Illustrators (1970), has compared the work of Leech to William Makepeace Thackeray: "Leech was a friend and admirer of Thackeray's in its light, humorous sketchiness; yet Leech, who had less formal training than Thackeray, demonstrates in every line he draws a more seeing eye. He has noticed how men tilt when moving and slump when sat, how they brace themselves, bend, and let themselves go; and he has noticed and noted innumerable faces and expressions. These atomic noticings, rapidly supervening on each other, have become cemented, transfused, and incorporated into an instinctive-seeming sense of the way the body would move and look in any given situation which he has perhaps not seen, but which he is required to imagine."

Leech became a close friend of Charles Dickens and the two men often went on holiday with Mark Lemon and John Forster. While in Bonchurch on the Isle of Wight, Leech had an accident. Peter Ackroyd points out in Dickens (1990): "John Leech, while bathing, was knocked over by a giant wave and suffered some kind of concussion... and leeches were placed upon his temples to draw off the blood. But he remained ill, restless, and in pain; until that is, Dickens offered to mesmerise him into a magnetic sleep. Which he did, successfully."

Simon Houfe has pointed out: "Between 1845 and 1862 Leech had acquired increasingly bigger London houses, where he lived in some style. The expense drove him to take on more work and this taxed his physical strength. The onset of angina was not helped by the constant pecuniary demands from his indigent father and importunate sisters. He developed a sensitivity to street noise, particularly music (a frequent subject of his work)."

John Leech died of a heart attack at the age of 47 on 29th October, 1864. He is buried at Kensal Green, London.

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