Several of his musical influences have been acknowledged in his songs such as "Williamsburg Will Oldham Horror", "The History of The Fall" and "The Chelsea Hotel Oral Sex Song", concerning the song by Leonard Cohen. Lewis' lyrics are complex and literate, often combining a nihilistic world-view with a hopeful message and sharp wit. Growing up on the Lower East Side of Manhattan Island his songs are also highly informed by his home surroundings, with songs namechecking places such as Williamsburg, the FDR Drive and the East River.
Jeff is often regarded as part of the US antifolk movement, first and foremost because he was one of the many bands and performers (including The Moldy Peaches, Major Matt Mason USA and Lach) who played in the 90s at New York's Sidewalk Cafe and its biannual antifolk festivals and anti-hoot open mic events. His music also possesses certain traits of a perceived antifolk style - a downbeat self-deprecating humour, an off-kilter singing style, a mixture of acoustic and 'punk' songs which feature themes of everyday occurrences and feelings. Jeff himself does not mind the 'antifolk' tag: “I think it’s a cool title. 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.”
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 and in 2003 he released the album It's the Ones Who've Cracked That the Light Shines Through. His third record, City and Eastern Songs, was released in the UK in November 2005 and in the US in September 2006. All three of these albums also include his brother, Jack Lewis, who wrote and sang a number of the songs. In October 2007, Jeffrey released 12 Crass Songs, an album consisting entirely of songs written by the anarcho-pacifist British punk band Crass, reworked to match Jeffrey's antifolk style.
Jeffrey has his own comic book series titled 'Fuff' (formerly called 'Guff') available via Olive Juice Music.
In June 2008 Jeffrey Lewis with his brother Jack were the support act for Steven Malkmus and the Jicks in Europe. Other well-known acts that Jeffrey (with or without his band) has performed shows or whole tours with include Devendra Banhart, Black Dice, Adam Green, Thurston 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, the Trachtenburg Family Slideshow Players, Wooden Wand, the Cribs, the Danielson Famile, Herman Dune, Los Campesinos, Giant Drag, Super Furry Animals and others.