Based in the 1820s, the orphan, young Oliver is born in a parish workhouse in an unnamed town. His unmarried mother dies during labour. Old Sally, who was present at the birth, takes from the dying woman a locket and ring. Mr Bumble, the Beadle, names the boy Oliver Twist. Oliver is sent to an orphanage, run by Mrs. Mann, until he is nine years old, when he is returned to the workhouse.
The orphans at the workhouse are starving because of their cruel treatment. They cast lots to decide who will ask for more gruel for them all, and Oliver is chosen. At evening supper, once the gruel is dished out and eaten, Oliver goes to the master and makes his famous request, "Please Sir. I want some more". He is then branded a troublemaker and offered as an apprentice to anyone willing to take him, and he is eventually apprenticed to Sowerberry, the undertaker. Oliver fights with Noah Claypole, an older boy at the undertakers, because Noah mocked Oliver's dead mother. Oliver is then beaten for the offence, but he manages to escape and runs away to London.
In London, Oliver meets Jack Dawkins, the Artful Dodger, who offers him a place to stay, where he meets up with Fagin and his band of young thieves. Oliver innocently goes "to work" with Dawkins and Charley Bates, but sees the real nature of their "work" when Dawkins picks the pocket of a gentleman. When the gentleman, Mr. Brownlow, realises he is being robbed, Oliver is mistaken for the pickpocket. And he is then chased, captured, and taken to the police. Oliver, who was injured in the chase, is cleared by a witness to the crime and is taken in by Brownlow to his home where he is well treated. After recovering from his injuries, Oliver is sent on an errand by Brownlow to pay a local merchant £5 and to return some books. However, Oliver is caught by Nancy and Bill Sikes, who pretend to be his siblings, and is returned to Fagin's den. However, Nancy later betrays Fagin and Sikes, as well as herself, for doing so since they've stolen Oliver's chance to have a better life.
Mr. Brownlow, who mistakenly thinks that Oliver has run away with the money, assumes that Oliver was a thief all along. This belief is further strengthened when Bumble, in response to Brownlow's newspaper advertisement for information about Oliver, gives a disparaging opinion of the boy. Despite this, Brownlow still holds onto a little bit of hope that this might not be true.
Meanwhile, Oliver is forced by Fagin to join Sikes in an attempted robbery at a rural house, as they need a small boy to enter a window and open the front door for Sikes to get in. However, the robbery fails and, in the ensuing chase, Oliver is shot. He is then nursed back to health at the home of the Maylies, the house Sikes was attempting to burgle. Oliver gives his story to the Maylies (more exactly, the widow Mrs. Maylie, her son Harry and her adoptive daughter Rose) and Doctor Losberne. He also helps out when Rose falls ill, casually meeting a mysterious man along the way.
The mysterious man is Mr. Monks, who is revealed to be Oliver's half brother (his true name being Edward Leeford JR.). He joins Fagin in an attempt to recapture Oliver and lead him into a life of crime, so that Oliver's rightful inheritance, of which Oliver knows nothing, would then go to Monks. Nancy, who still feels compassion for Oliver, overhears Fagin's and Monk's plans and tells Rose Maylie, hoping to thwart them. Rose then contacts Brownlow (clearing Oliver's name in the process, much to Brownlow's relief), Dr. Losberne and other people, to help her protect Oliver.
Meanwhile, Bumble has married the matron of the workhouse, Mrs. Corney. The former Mrs. Corney had been in attendance at Old Sally's death, and purloined the locket and ring Old Sally had taken from Oliver's mother Agnes on her deathbed. Monks buys these items from the Bumbles and throws them into the river Thames, hoping that, by destroying them, Oliver's true identity will remain hidden.
Brownlow and Rose Maylie meet Nancy on London Bridge and she tells them how to find Monks. However, Fagin has had Nancy followed and, believing Nancy has revealed his secrets, Fagin tells Sikes that Nancy has betrayed them. Sikes brutally murders Nancy, then flees London to the country. However, their neighbors and some of Fagin's own band members soon find out about Nancy's death and, enraged, they tell the police; Sikes falls to his death when he's about to be captured and taken away.
Oliver is revealed to be the illegitimate son of a rich man named Edwin Leeford SR. and his young mistress, a girl named Agnes Fleming. Leeford had also fathered another son, Edward JR. ("Monks"), through a failed former marriage. After seducing Agnes, Leeford died, leaving a will which stated that the unborn child would inherit his estate if "in his minority he should never have stained his name with any public act of dishonour, meanness, cowardice, or wrong" in the event of which all would go to Monks. Monks is given half of Oliver's inheritance in cash by Brownlow--who had been Edwin Leeford's best friend and the keeper of his secrets--in the hope that he would start a new life. Monks flees to the United States, where he quickly squanders the money and dies in prison.
Rose Maylie is revealed to be Agnes Fleming's younger sister, who was adopted by the Maylies after her parents died. Therefore, Rose is Oliver's aunt and is able to marry Harry Maylie. Oliver collects his inheritance and is adopted by Brownlow, for the conventional happy ending to the novel.