[5] Starting in 2000, he spent about two years living in Austin, Texas, playing open mic nights, working odd jobs and distributing his autobiographical comics to local coffee shops.

Lewis' lyrics are complex and literate, often combining a nihilistic world-view with a hopeful message and sharp wit.

Lewis is often regarded as part of the antifolk movement,[6] foremost because he was one of the many bands and performers (including The Moldy Peaches, Kimya Dawson, Diane Cluck, Regina Spektor, Major Matt Mason USA and Lach) who played in the 1990s at New York's SideWalk Cafe and its biannual antifolk festivals and open mic events.

The fact that no one knows what it means, including me, makes it kind of mysterious and more interesting than saying that you're a singer/songwriter or that you play indie rock.

"[7] After being signed by the British record label Rough Trade in 2001, Jeffrey Lewis released his first official album The Last Time I Did Acid I Went Insane.

Other well-known acts that Lewis has performed shows or whole tours with include The Presidents of the United States of America, Devendra Banhart, Jarvis Cocker, Black Dice, Adam Green, Thurston Moore, R. Stevie Moore, the Fall, Kimya Dawson, Beth Orton, Frank Black, the Fiery Furnaces, Daniel Johnston, Scout Niblett, the Mountain Goats, Dr. Dog, The Moldy Peaches, Cornershop, Trachtenburg Family Slideshow Players, Wooden Wand, the Cribs, Danielson, Herman Dune, Los Campesinos, Roky Erickson, and Super Furry Animals.

[10][9] Lewis has created a number of illustrated historical songs, usually sung while flipping through accompanying books of color drawings, including ten such pieces which are in use by The History Channel on their website.

In 2021 the Complete Fuff Comix Collection was released, a bundle of all 13 issues with an exclusive dust jacket and 3 page bonus comic.