Ligotti started his career as a published writer in the early 1980s with a number of short stories published in various American small press magazines. He was contributing editor to Grimoire from 1982-1985. 
His unique and affecting tales gathered a small following. Ligotti's relative anonymity and reclusiveness led to speculation about his identity. In an introduction to a collection of Ligotti fiction, The Nightmare Factory (1996), Poppy Z. Brite mentioned these notions with a rhetorical question: "Are you out there, Thomas Ligotti?"
In recent years, Ligotti has conducted interviews and disclosed some details of his background. For 23 years Ligotti worked as an Associate Editor at Gale Research (now the Gale Group), a publishing company that produces compilations of literary (and other) research. In the summer of 2001, Ligotti quit his job at the Gale Group and moved to south Florida. His favorite music is generally instrumental rock.
Ligotti's worldview has been described[by whom?] as profoundly nihilistic (though he is wary of the label, stating: "'Nihilist' is a name that other people call you. No intelligent person has ever described or thought of himself as a nihilist."), and has stated he has suffered from chronic anxiety for much of his life; these have been prominent themes in his work.
Ligotti has stated he prefers short stories to longer forms, both as a reader and writer, though he has written a novella, My Work Is Not Yet Done (2002)
Ligotti collaborated with the musical group Current 93 on the albums In a Foreign Town, In a Foreign Land (1997, reissued 2002), I Have a Special Plan for This World (2000), This Degenerate Little Town (2001) and The Unholy City (2003), all released on David Tibet's Durtro label. Tibet has also published several limited editions of Ligotti's books on Durtro Press. Additionally, Ligotti played guitar on Current 93's contribution to the compilation album Foxtrot, whose proceeds went to the treatment of musician John Balance's alcoholism.
Wonder Entertainment released The Frolic: Collector's Edition DVD and Book set, which contains a short film adaptation of Thomas Ligotti's short story "The Frolic". This collector's edition contains the following: commentary tracks and behind-the-scenes by director Jacob Cooney, producer Jane Kelly Kosek, and actor Maury Sterling; a new interview with screenwriters Thomas Ligotti and Brandon Trenz; a newly revised version of the short story, with a new introduction by Thomas Ligotti; and the screenplay, with a new introduction by Brandon Trenz. Only 1,000 copies were made available of this collector's edition. The book, which contains the revised "The Frolic", is exclusive to this set.
Ligotti gives a favorable quote in the introduction to Nova Scotia, Canada, fiction writer Barry Wood's short story "Nowhere to Go" (2008) published in Postscripts #14. Ligotti has also provided blurbs for books by Eddie M. Angerhuber, Matt Cardin, Michael Cisco, John B. Ford, the philosopher Eugene Thacker, and Thomas Wiloch. Scottish philosopher Ray Brassier wrote the Foreword to Ligotti's The Conspiracy Against the Human Race: A Contrivance of Horror (2010).
Subterranean Press has begun to release definitive revised editions of some of Ligotti's earlier collections, including Grimscribe. In 2014, the Subterranean Press also published two new works by Ligotti: The Spectral Link, which includes two brand new stories (the first from Ligotti's pen in more than a decade), and Born to Fear: Interviews with Thomas Ligotti, edited by Matt Cardin and bringing together interviews with Ligotti spanning the previous 25 years, including several that had not previously appeared in English.
In 2014, the HBO television series True Detective attracted attention from some of Ligotti's fans because of the striking resemblance between the pessimistic, antinatalist philosophy espoused in the first few episodes by the character of Rust Cohle (played by Matthew McConaughey) and Ligotti's own philosophical pessimism and antinatalism, especially as expressed in The Conspiracy Against the Human Race. The series' writer, Nic Pizzolatto, confirmed that Ligotti, along with several other writers and texts in the weird supernatural horror genre, had indeed influenced him. Pizzolatto said he found The Conspiracy Against the Human Race to be "incredibly powerful writing". On the topic of hard-boiled detectives, he asked: "What could be more hardboiled than the worldview of Ligotti or [Emil] Cioran?"
Studies in Modern Horror, issue #2 (2004), edited by N. G. Christakos. This issue of the scholarly journal concerning contemporary weird tales includes Nick Curtis' essay "Notes on Time Displacement and Memory Loss in Crampton" and the first printed version of The Unholy City poem cycle by Ligotti.
Studies in Modern Horror, issue #4 (2006), edited by N. G. Christakos. This issue of the scholarly journal concerning contemporary weird tales includes Stephen Tompkins' essay, The Nemesis of Mimesis: Thomas Ligotti, Worlds Elsewhere, and the Darkness Ten Times Black.
The Grimscribe’s Puppets edited by Joseph S. Pulver, a collection of tales in tribute to and based upon Ligotti (Miskatonic Press 2013).