Lewis gained prominence in the 1980s as a child actress, appearing in the films Troop Beverly Hills (1989) and The Wizard (1989) and the television series Brooklyn Bridge (1991–93).

In the mid-1990s, Lewis semi-retired from acting to focus on her musical career, and formed Rilo Kiley in 1998 with fellow former child actor Blake Sennett.

[3] Lewis has released five solo albums: Rabbit Fur Coat (2006), Acid Tongue (2008), The Voyager (2014), On the Line (2019), and Joy'All (2023).

In addition to Rilo Kiley and her solo career, Lewis has been a member of The Postal Service, Jenny & Johnny, and Nice as Fuck.

She also had small roles on TV shows, such as Murder, She Wrote; The Twilight Zone (1985); Baywatch; The Golden Girls; Growing Pains; Just the Ten of Us; Roseanne; Mr. Belvedere; and Brooklyn Bridge.

In 1998, Lewis and friends Pierre De Reeder, Dave Rock, and then-boyfriend Blake Sennett formed the band Rilo Kiley.

In an interview with NPR's All Songs Considered, Lewis remarked that she wanted to name the group Love's Way (after her parents' lounge act in Las Vegas), but Sennett "didn't go for it.

With her endless supply of cool sunglasses, vintage dresses, and hats ... she was a beacon of hope for introspective teens ... as a microgenerational sad-girl touchstone, many of us have our own Jenny Lewis Anecdote, our lives touched by her magnificent tweeness in different ways.

Described by Lewis as "a kind of soul record"[citation needed], Rabbit Fur Coat (released January 24, 2006) features contributions from Oberst, M. Ward, and Maroon 5 guitarist James Valentine.

The album received positive reviews, with Entertainment Weekly writing, "Consider Lewis the Emmylou Harris of the Silverlake set"[20] and Rolling Stone commenting that "her girlishly seductive vocals are more versatile than ever".

[26] The music video for "Just One of the Guys" was released on July 15, 2014, through GQ and stars Lewis, Anne Hathaway, Kristen Stewart, Brie Larson, and Tennessee Thomas, former drummer of The Like (now disbanded).

[30] The album was produced by Dave Cobb, who Lewis met while visiting Lucius at RCA Studio A in Nashville, Tennessee.

In 2007, Lewis contributed vocals to various songs on Johnathan Rice's album Further North, and she appeared in the music video for "We're All Stuck Out In The Desert (And We're Gonna Die)".

Later that year, Lewis voiced the role of the assistant director for Walt Disney Pictures' animated film Bolt (2008), and she also provided the song "Barking at the Moon".

[34] In 2014, Lewis contributed an exclusive track to HBO's Girls, in collaboration with Vampire Weekend's Rostam Batmanglij titled "Completely Not Me".

[38] On November 13, 2019, it was announced Lewis would be an opening act for Harry Styles on the North American leg of his 2020 Love On Tour.

[40] In 2010, Lewis formed the duo Jenny and Johnny with her then-boyfriend, musician Johnathan Rice, and the pair released an album titled I'm Having Fun Now on Warner Bros. Records.

In 2016, the trio Nice as Fuck, comprising Lewis, Erika Forster (of Au Revoir Simone), and Tennessee Thomas (of The Like), debuted at a Bernie Sanders benefit.