After the father of a family dies, leaving the wife and children with no source of income, Nicholas Nickleby, with his mother and his younger sister Kate, travel to London to seek help from their wealthy but cold-hearted uncle Ralph, a money-lender. Ralph arranges for Nicholas to be hired as a tutor, and finds Kate work as a seamstress. Nicholas meets his new employer Mr. Squeers just as he concludes his daily business with Mr. Snawley, who is "boarding" his two unwanted stepsons.
Nicholas is horrified to discover that his employers, the sadistic Mr. and Mrs. Squeers, run their boarding school, Dotheboys Hall in Yorkshire, like a prison. They physically, verbally, and emotionally abuse their young charges on a regular basis. Nicholas eventually rebels and escapes, taking with him young friend – the crippled Smike.
Nicholas and Smike take lodgings with Newman Noggs, Ralph Nickleby's clerk. Nicholas tries to find a job, but rejects a low-paying position as a politician's secretary. A job as a tutor of French for the Kenwig daughters comes to comic disaster. He and Smike decide to search for work elsewhere. As they are leaving the city, they make the acquaintance of Madeline Bray, the sole support of her father, who gambled away his fortune and now is indebted to Nicholas's uncle.
In search of food and lodging, they stop at an inn, and the proprietor introduces them to actor-manager Vincent Crummles, who owns and operates a travelling theatrical troupe with his actress wife. Crummles hires the two as actors and casts them in a production of Romeo and Juliet, in which they are successful.
Nicholas decides to return to London after he receives a letter from Noggs, who urges him to come back as quickly as possible as his uncle has put his sister in great jeopardy despite his promise to make certain they come to no harm. Kate has been subjected to unwanted attention from Sir Mulberry Hawk and Lord Verisopht, clients of her uncle, and when Nicholas overhears them bawdily discussing her in a tavern he is determined to defend his sister's honour. Hawk refuses Nicholas's demand to "step outside", and they fight in Hawk's carriage, resulting in an accident in which Hawk is injured. Hawk and Lord Verisopht argue over Hawk's lack of honour, and Hawk kills Lord Verisopht in a duel with pistols. As a result, Ralph Nickleby loses £6,000, owed to him by Verisopht, much to the delight of Noggs, who harbours a hidden desire for revenge against his employer.
Nicholas then finds employment as a clerk with the portly, benevolent, twin brothers Cheeryble, whose nephew Frank begins to court Kate. They provide him a cottage in which Nicholas can place his family and Smike, who has been accepted warmly by all. Meanwhile, Squeers returns to , planning to capture Smike and bring him back to Dotheboys Hall, and is engaged by Ralph Nickleby to stalk Nicholas and Smike. Squeers and Mr. Snawley make off with Smike "on the wishes of his father". Nicholas, aided by Noggs, intercepts them and foils the plot. Smike, severely beaten by Squeers, is nursed by Kate and falls in love with her.