Reade became a fellow of Magdalen College, Oxford, in 1835 but treated the position as a sinecure. In 1843 he was called to the bar but never practiced law, and several years later he became a dealer in violins. Finally, in 1849 he embarked on a long career as a dramatist, theatre manager, and novelist. Laura Seymour, an actress, lived with him from 1856 until her death in 1879.

Reade's novels reveal his concern with social issues. It Is Never Too Late to Mend (1856) attacked conditions in prisons, and Hard Cash (1863) exposed the ill-treatment of mental patients, especially in private asylums; Put Yourself in His Place (1870) dealt with the coercive activities of trade unionists. Foul Play (1868), written with Dion Boucicault (Boucicault, Dion), revealed the frauds of “coffin ships” (unseaworthy and overloaded ships, often heavily insured by unscrupulous owners) and helped to sway public opinion in favour of the safety measures proposed later by Samuel Plimsoll; like many of Reade's fictions, it had a dual identity as novel and play. The historical novel Griffith Gaunt (1866) was widely attacked for its sexual frankness. In an effort to increase the realism in his novels, Reade loaded—or, as his critics complained, overloaded—them with carefully researched detail.