Humphry Clinker is an epistolary novel, a collection of letters, that charts the adventures of a family group traveling through Britain. The head of the family is Matthew Bramble, a gouty old man, who is constantly writing his doctor with his complaints and visiting areas supposed to be good for his condition. He is accompanied by his niece, Lydia, who is in love with a poor man, Wilson. Her brother, an Oxford student, also comes along, as does Bramble's unwed sister, Tabitha. Tabitha's maid, Winifred Jenkins, accompanies her.

The group travels to Bath, London, Edinburgh, and the Scottish Highlands. Along the way, they meet Humphry Clinker, a dull-headed creature who becomes devoted to Matthew Bramble, even saving his life. He turns out to be Bramble's illegitimate son. Lydia's lover is discovered to be the son of a wealthy man who is Bramble's friend; they are finally happily married.

Tabitha marries Lismahago, an eccentric captain. Winifred Jenkins joins the festivities by marrying Clinker. Relieved of the feminine presence and bother in his life, Bramble recovers his health, writing to his doctor that from now on he will go hunting rather than write letters.