Clarissa's older sister, Arabella, begins to be courted by Robert Lovelace, a wealthy “libertine” and heir to a substantial estate. However, she rejects him because she felt that he put more effort into gaining the approval of her parents than in wooing her and felt disrespected by this. Lovelace quickly moves on from Arabella to Clarissa, much to the displeasure of Arabella and their brother James Harlowe. Despite Clarissa's insistence in her dislike for Lovelace, Arabella grows jealous of her younger sister for Lovelace's interest in her. James, also, dislikes Lovelace greatly because of a duel which had occurred between the two of them. These feelings combine with resentment that Clarissa was left a piece of land by their grandfather and lead to aggression towards Clarissa from her siblings. It is proposed that Clarissa marry Roger Solmes, a match that the entire Harlowe family, except Clarissa, accepts. Clarissa, however, finds Solmes to be unpleasant company and does not wish to marry him. This makes her family suspicious of her feelings towards Lovelace, and they begin acting paranoid towards her insistence that she does not care for Lovelace either.
The Harlowes begin restricting Clarissa's access to the outside world by forbidding her to see Lovelace anymore and eventually forbidding her to either leave her room or send letters to her friend, Anna Howe, until Clarissa apologizes and agrees to marry Solmes. Feeling trapped and desperate to regain her freedom, Clarissa continues to communicate with Anna in secret and begins a correspondence with Lovelace, while trying to convince her parents not to force her to marry Solmes. Neither Clarissa nor her parents will concede, leading to a communication breakdown and her parents' disregard of Clarissa's protests as stubborn disobedience. Lovelace convinces Clarissa to elope with him to avoid her conflict with her parents. Joseph Leman, a servant of the Harlowes, shouts and makes noise so it may seem like the family has awoken and discovered that Clarissa and Lovelace are about to run away. Frightened of the possible aftermath, Clarissa leaves with Lovelace but becomes his prisoner for many months. Her family now will not listen to or forgive Clarissa because of this perceived betrayal, despite her continued attempts to reconcile with them. She is kept at many lodgings, including unknowingly a brothel, where the women are disguised as high-class ladies by Lovelace so as to deceive Clarissa. Despite all of this, she continues to refuse Lovelace, longing to live by herself in peace.
Lovelace, during this time, is desperate to destroy Clarissa's morals, despite his declaration that he loves her. He puts increasing pressure on her to compromise her morals in an attempt to prove that virtuous women do not exist; Clarissa, however, does not waver. Lovelace at last gains entry to Clarissa's bedroom, under the pretence of saving her from a fire, but is thwarted from seduction or rape by her extreme resistance to his physical advances. She agrees, under threat of rape, to forgive and marry him; however, she instead makes her first successful escape from him.
Enraged by Clarissa's flight, Lovelace vows to seek revenge. He hunts her down to the lodgings in which she is hiding, and engages all the rooms around her, effectively trapping her, while he plots to gain her trust by introducing her to respectable members of his family. These are actually hired impersonators. During this time he intercepts a letter to Clarissa from Anna Howe that would expose the true extent of his deception and roguery. He commits forgery to put an end to the communication between them.
Eventually, he persuades Clarissa to accompany his imposter-relatives out in a carriage, and thus carries her back to the disguised brothel. There, with the assistance of the prostitutes and brothel madam, he drugs and rapes her.
After the rape, Clarissa suffers a loss of sanity for several days, presumably brought on by her extreme distress as well as the dose of opiates administered to her. (This temporary insanity is represented in her "mad letters" by the use of scattered typography.)
When Clarissa recovers her senses, Lovelace soon realises that he has failed to "subdue" or corrupt her; instead, she is utterly repulsed by him, repeatedly refusing his offers of marriage, despite her precarious situation as a now-fallen woman. She accuses him of deceiving and unlawfully detaining her, and insists that he set her free, but he continues to claim that the impersonators really were his family members, and that his crime was simply one of desperate passion. He alternates between making threats, and professions of love, to convince her to marry him. She steadfastly resists, and attempts to escape him several times.
Lovelace is forced to concede that Clarissa's virtue remains untarnished, but he begins to convince himself that the "trial" was not properly conducted, since his victim was drugged at the time, and could give neither her consent nor refusal. He decides to orchestrate a second rape, this time without the use of opiates. Affecting to be angered by the discovery that she has bribed a servant to aid her escape, Lovelace begins to menace Clarissa, intending to escalate the confrontation to physical violence, but she majestically condemns his premeditated villainy, and threatens to kill herself with a pen-knife should he proceed. Utterly confounded by her glorious presence and righteous indignation, and terrified by her willingness to die for her virtue, Lovelace retreats.
Lovelace is now more intent than ever to make Clarissa his wife, but he is called away to attend his dying uncle, from whom he is expecting to inherit an Earldom. He charges the prostitutes to keep Clarissa detained, but well-treated, until he can return to secure her in marriage. However, while he is away, Clarissa manages to escape from the brothel. She is jailed for a few days following a charge by the brothel madam for unpaid bills, is released, and finds sanctuary with a shopkeeper and his wife. Corresponding with Lovelace's real family, she discovers for herself the true extent of his deception. She lives in constant fear of again being accosted by Lovelace who, through one of his close associates and also a libertine, John Belford, as well as through his own family members, continues to offer her marriage, to which she is determined not to accede. She becomes dangerously ill due to the mental duress, rarely eating, convinced that she will die soon.
As her illness and probable anorexia progresses, she and John Belford become correspondents, and she appoints him the executor of her will as she puts all of her affairs in order, to the alarm of the people around her. Belford is amazed at the way Clarissa handles her death and laments what Lovelace has done. In one of the many letters sent to Lovelace, he writes, "if the divine Clarissa asks me to slit thy throat, Lovelace, I shall do it in an instance." Eventually, surrounded by strangers and her cousin, Col. Morden, Clarissa dies in the full consciousness of her virtue and trusting in a better life after death. Belford manages Clarissa's will and ensures that all her articles and money go into the hands of the individuals she desires should receive them.
Lovelace departs for Europe, and his correspondence with his friend Belford continues. During their correspondence, Lovelace learns that Col. Morden has suggested he might seek Lovelace and demand satisfaction on behalf of his cousin. He responds that he is not able to accept threats against himself and arranges an encounter with Col. Morden. They meet in Munich and arrange a duel. The duel takes place, both are injured, Morden slightly, but Lovelace dies of his injuries the following day. Before dying he says "let this expiate!"
Clarissa's relatives finally realize the misery they have caused but discover that they are too late and Clarissa has already died. The story ends with an account of the fate of the other characters.