Born in Bethesda, Maryland, and raised in Dallas, Texas, Loeb attended The Hockaday School, an all-girls private school in Dallas. She has three siblings -- Benjamin Loeb, Debbie Loeb, and Philip Loeb. After graduating from high school in 1986, she went to Brown University where she graduated in 1990 with a degree in comparative literature. At Brown, she and Elizabeth Mitchell formed a band named Liz and Lisa, featuring future singer/songwriter and Brown classmate Duncan Sheik as a guitarist as well as the upcoming influential jazz/rock bassist Rick Lassiter while contemplating band names such as Nine Stories and Soto Voce'. The duo released the albums Liz and Lisa and Liz and Lisa - Days Were Different independently. Loeb had developed a following from her solo acoustic performances on the New York City coffeehouse circuit, where she sold a collection of her songs referred to as The Purple Tape.
Loeb's big break came when she was discovered by actor and friend Ethan Hawke, who lived in an apartment across the street from her in New York City. She met Hawke through mutual friends in the NYC theatre community. Hawke gave a tape of Loeb's song "Stay (I Missed You)" to director Ben Stiller during the making of the 1994 film Reality Bites. Stiller subsequently agreed to use the song in the film and on the film's soundtrack. "Stay" ultimately went on to become a number one hit on the American charts. When her song hit number one, Loeb earned the distinction of being the only artist to top the Hot 100 before being signed to any record label.
In September 1995, Loeb's debut album, Tails, was released. The album was co-produced by Juan Patiņo, her longtime then-boyfriend. Although none of the singles from Tails could quite match the breakthrough appeal of "Stay" (which was also included on this album), Loeb still managed a Top-Twenty hit with "Do You Sleep?" and two moderately successful radio hits with "Taffy," and "Waiting for Wednesday." Tails went on to achieve platinum status.
In 1997, a second major-label album, Firecracker, was released. Though critically praised, it did not have the commercial success of Tails, but the single "I Do" was very popular on radio (it charted in the Top Twenty) and music television. The song "How" featured in the soundtracks for the films Twister and Jack Frost, and was featured in the Buffy episode Homecoming. "Let's Forget About It" was released as a single. At this point Loeb dropped the name of her support band, Nine Stories, and performed under her own name. "Firecracker" went Gold.
In 2000 she participated on the Ozzy Osbourne tribute album Bat Head Soup performing Goodbye to Romance with Dweezil Zappa on guitar.
Loeb's next project was Cake and Pie the release of which was delayed until 2002. The album was a commercial failure (despite excellent reviews) and did not receive any major backing or promotion from her record label. She was eventually dropped, and she bought the rights to the masters of the songs from that album. It was re-released by Artemis Records in late 2002, with the songs rearranged and some deletions/additions. Featuring new packaging, it was retitled Hello Lisa. A children's album called Catch the Moon was independently released in 2003. Videos from this album have been featured on the Noggin TV network for children, alongside those of Laurie Berkner and Dan Zanes, rockers who have crossed over much further into the children's music field.
In May 2004, Loeb announced that her longtime relationship with Dweezil Zappa was over. In 2004, Loeb changed record labels once again, due to a lack of promotion from her former label, Artemis Records. She was signed to the independent label Zoe/Rounder, and The Way It Really Is was released August 2004. The album was Loeb's fifth studio-recorded album.
Her latest album, The Very Best of Lisa Loeb, was released in January 2006.
More recently, Loeb has contributed vocals to New Found Glory's cover of Stay, which will feature on their 2007 LP From the Screen to Your Stereo Pt. 2.
When not touring, or doing other promotional work, she resides in Los Angeles.
Loeb has done several guest appearances on popular television shows, such as The Nanny in 1997. In 1998, she played the voice of a newborn baby in The Rugrats Movie and played a musician in an episode of Cupid. In 1999, Loeb was featured as a news reporter in the horror film House on Haunted Hill. In 2004, she was featured in Serial Killing 101. On January 16, 2004, her reality show Dweezil & Lisa first aired on Food Network, in which she shared title billing with her longtime boyfriend Dweezil Zappa. In 2005, she appeared on The Colbert Report as herself as part of a small gag in which the eponymous host could not remember all the lyrics of "Stay," and asked Loeb, who was standing by a camera with her guitar, how it went. She sang and strummed a little to jog Colbert's memory.
She has been the voice of Mary Jane Watson in the animated show Spider-Man: The New Animated Series, broadcast on MTV.