Clarissa Harlowe, the tragic heroine of Clarissa, is a beautiful and virtuous young lady whose family has become wealthy only recently and now desires to become part of the aristocracy. Their original plan was to concentrate the wealth and lands of the Harlowes into the possession of Clarissa's brother James Harlowe, whose wealth and political power will lead to his being granted a title. Clarissa's grandfather leaves her a substantial piece of property upon his death, and a new route to the nobility opens through Clarissa's sister, Arabella, marrying Robert Lovelace, heir to an earldom. After being rejected, Lovelace begins to court Clarissa. James, who dislikes him personally, provokes a duel with Lovelace, who is seen thereafter as the family's enemy. James also proposes that Clarissa marry Roger Solmes, who is willing to trade properties with James to concentrate James's holdings and speed his becoming Lord Harlowe. The family agrees and attempts to force Clarissa to marry Solmes, whom she finds physically disgusting as well as boorish.
Desperate to remain free, she begins a correspondence with Lovelace. When her family's campaign to force her marriage reaches its height, Lovelace tricks her into eloping with him. Joseph Leman, the Harlowes' servant, 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. She is kept at many lodgings and even a brothel, where the women are disguised as high-class ladies by Lovelace. She refuses to marry him on many occasions, longing to live by herself in peace. She eventually runs away but Lovelace finds her and tricks her into returning to the brothel.
Lovelace intends to marry Clarissa to avenge her family's treatment of him and wants to possess her body as well as her mind. He believes if she loses her virtue, she will be forced to marry him on any terms. As he is more and more impressed by Clarissa, he finds it difficult to believe that virtuous women do not exist.
The pressure he finds himself under, combined with his growing passion for Clarissa, drives him to extremes and eventually he rapes her by drugging her. Through this action, he believes that Clarissa must accept and marry him. It is suspected that Mrs. Sinclair (the brothel manager) and the other prostitutes assist Lovelace during the rape. (Clarissa's temporary loss of sanity caused by the rape is represented by an innovative use of scattered typography.)
Lovelace's action backfires, and Clarissa is more adamantly opposed to marrying a vile and corrupt individual like Lovelace. Eventually, Clarissa manages to escape from the brothel but Lovelace finds her and by deception manages to get her back to the brothel. She escapes a second time, is jailed for a few days following a charge by the brothel owner for unpaid bills, is released and finds sanctuary with a shopkeeper and his wife. 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.
As her illness progresses, she and John Belford become friends and she appoints him the executor of her will. She is dying and is determined to accept it and proceeds to get all her affairs in order. Belford is amazed at the way Clarissa handles her approaching 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 realise 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.