The central character, John Melmoth (a Wandering Jew type), is a scholar who sells his soul to the devil in exchange for 150 extra years of life and spends that time searching for someone who will take over the pact for him. The novel actually takes place in the present, but this back story is revealed through several nested stories-within-a-story that work backwards through time (usually through the Gothic trope of old books).
The novel was cited by Karl Edward Wagner as one of the thirteen best supernatural horror novels, and by H. P. Lovecraft as "an enormous stride in the evolution of the horror-tale".. The novel, which is usually considered to be the last great work of "high Gothic" fiction, goes beyond being just an entertaining horror plot. It offers some insightful social commentary on early nineteenth century England and, throughout the novel, it bitterly attacks Roman Catholicism while expounding the virtues of Protestantism's comparative unassuming simplicity.
The story was one of the many inspirations for the Anne Rice novel Memnoch the Devil.
Humbert's car in Vladimir Nabokov's Lolita was named Melmoth, presumably because he uses it to wander from place to place with Lolita, who is an admixture of blessing and curse.
In the Metabaron spin-off to the Incal comic. The Metabaron known as Steelhead encounters and enter a symbiotic relationship with an ancient poet known as Melmoth. This Melmoth had also lived unnaturally long due to artificial means. His pact with Steelhead can be compared to making a pact with the devil.