According to Spin magazine, Velez was born in 1967 in Hell's Kitchen in New York City as the youngest of ten to a religious mother, who supported the family by babysitting, and an absentee father. Of Puerto Rican descent, Velez learned to speak Spanish at home and English in school. She sang in her church choir, at the Church of the Sacred Heart of Jesus, along with her six sisters, and was an A student at Julia Richman High School in Manhattan. In school she was also part of a traveling singing group that sang Motown hits and songs from old Broadway musicals.

With Hughes and Alex "Spanador" Moseley, Lisa Lisa and Cult Jam recorded their debut single, "I Wonder If I Take You Home," soon after forming in 1985, releasing it as an independent single. The group quickly signed to Columbia Records, which re-released the single, and it climbed into the R&B top ten in the US and the top 20 in the UK. The group amassed a number of hit songs throughout the 1980s.

Velez said of her moniker "I guess they had the type of idea like, okay, [the U.T.F.O. hit] 'Roxanne, Roxanne' worked, why not Lisa Lisa? I thought it was cute because I knew it would cause controversy, talk." About getting paid, Velez expressed "I don't think about the money. I'm not doing this for the money. I was pulling in 600 to 700 a week when I was working at Benetton, so it doesn't mean shit to me. I'm just doing this 'cause I want to sing." By the end of the '80s, however, the group's success had begun to decline. Their fourth and final album, Straight Outta Hell's Kitchen, was less of a commercial success, though it did include a hit with "Let the Beat Hit 'Em," which reached the top 40 on the US pop chart and was a hit on both the R&B and club charts. The group disbanded in 1991, and Velez pursued both solo singing and acting careers, and Moseley and Hughes went on to do other projects.

Lisa Lisa released a solo album called LL77 in 1994, which included the moderate club hit "When I Fell In Love" (which was remixed by Junior Vasquez) and the notable single "Skip to My Lu", which hit No. 38 on the R&B chart. She resurfaced circa 2001 on the Nickelodeon series Taina, in which she played the title character's mother. On June 24, 2008, Lisa Lisa presented an award at the BET Awards sparking interest that she may be plotting a comeback. In 2009, she released Life 'n Love, a full-length album of new material on Mass Appeal Entertainment featuring the single "Can't Wait" with guest Rapper Pitbull. The album also features a cover version of the song "Stand" which was originally performed by Taylor Dayne on her 1998 album Naked without You. In March 2014, she appeared with Stevie B., TKA, Sa-Fire, and others at the eighth annual Forever Freestyle showcase at the Lehman College Center for the Performing Arts in the Bronx.