It charts numerous sordid, tragic, and bizarre incidents that took place in and around Jackson County, Wisconsin between 1885 and 1900, primarily in the town of Black River Falls.

The events are outlined through actual written historical documents—primarily articles published in the town newspaper—with additional narration by Lesy, as well as excerpts from works by Hamlin Garland, Sinclair Lewis, and Glenway Wescott, which thematically parallel the incidents depicted.

In addition to a disintegration of the local economy after the closure of several industrial mines, the populace is plagued by a diphtheria epidemic that claims the lives of numerous children, as well as a series of violent crimes, murders, suicides, arsons, religious delusions, mental illness, and superstitions.

The book emphasizes the harsh elements of Midwestern rural life during the expansion of the American Frontier and imminent urbanization, and their role in sordid incidents that unfolded in and around the community.

"[6] In the years following its publication, Wisconsin Death Trip developed a cult following and has been cited as an inspiration for numerous other works of music, literature, and film.

[7][8] The book inspired a number of musical works, including the opera Black River by Conrad Susa, which was composed in 1975 and revised 1981; the 1999 "dramatic cantata" Songs of Madness and Sorrow by Daron Hagen; and the 1999 album Wisconsin Death Trip by the industrial metal band Static-X.

[9] Most recently, the book was adapted into a bluegrass/roots-rock opera by Tim Raphael and composer Jeff Berkson, which had its world premiere at Georgetown University's Davis Performing Arts Center on February 1, 2008.

The American author Stewart O'Nan "acknowledges his great debt to Michael Lesy," citing Wisconsin Death Trip as an inspiration for his novel A Prayer for the Dying.

In commentary on the two-disc DVD release of the Bob Dylan biopic I'm Not There, director Todd Haynes said that much of the imagery for the town of Riddle in the Richard Gere segment of the film was inspired by Lesy's book.