The group arrived on the music scene in 1992 with the album Ooooooohhh... On the TLC Tip. With four singles, it sold six million copies worldwide, leading to the group becoming a household name. Two years later CrazySexyCool was released, selling over 23 million copies worldwide, and cemented TLC as one of the biggest female groups of all time. TLC's third album, FanMail, was released in 1999 and sold over 14 million copies worldwide. Its title was a tribute to TLC's loyal fans and the sleeve contained the names of hundreds of them as a "thank you".

Lopes was often vocal about her personal life and difficult past. She readily admitted that she had come from an abusive, alcoholic background and struggled with alcoholism herself. These problems became headline news in 1994, when she set fire to Andre Rison's tennis shoes in a bathtub, which ultimately spread to the mansion they shared and destroyed it. She claimed that Rison had beaten her after a night out, and she set fire to his shoes to get back at him but that burning down the house was an accident. Lopes later revealed that she did not have a lot of freedom within the relationship and that Rison abused her emotionally and physically; she said that she released her frustrations about the relationship on the night of the fire.

In 1996, Lopes created the UNI Studios for the purpose of recording solo projects. Lopes' family opened the studio to the public. Her brother Ronald is the general manager of the studio. Lopes had a dream of making new artists able to record music at a low cost, in a high-end studio at her house. Her family continues to operate it and fill it with new equipment.

In 1998, Lopes hosted the short-lived MTV series, The Cut, in which a handful of aspiring pop stars, Rappers, and rock bands competed against each other in front of judges. The show's winner, which ended up being a male-female rap duo named Silky, was promised a record deal and funding to produce a music video, which would then enter MTV's heavy rotation. A then-unknown Anastacia finished in third place, but ended up securing a record deal after Lopes and the show's three judges were impressed by her performance.

During the recording of FanMail, a public conflict began amongst the members of the group. In the May 1999 issue of Vibe magazine, Lopes said, "I've graduated from this era. I cannot stand 100 percent behind this TLC project and the music that is supposed to represent me." In response to Lopes' comments, Watkins and Thomas stated to Entertainment Weekly that Lopes "doesn't respect the whole group" and "Left Eye is only concerned with Left Eye." In response, Lopes sent a reply through Entertainment Weekly issuing a "challenge" to Watkins and Thomas to release solo albums and let the public decide who was the "greatest" member of TLC:

After the release of FanMail, Lopes began to expand her solo career. She became a featured Rapper on several singles, including Spice Girl Melanie C's "Never Be the Same Again", which topped the charts in 35 countries, including the United Kingdom. She was also featured on "U Know What's Up", the first single from Donell Jones' second album, Where I Wanna Be, and she rapped a verse in "Space Cowboy" with NSYNC on their 2000 album, No Strings Attached. On October 4, 2000, Lopes co-hosted the UK's MOBO Awards with Trevor Nelson, where she also performed "U Know What's Up" with Jones. She also collaborated on "Gimme Some" by Toni Braxton for her 2000 album The Heat. She had previously featured on Keith Sweat's song "How Do You Like It". In 2001, she appeared in a commercial for Gap. In July 2001, Lopes appeared on the singers' edition of Who Wants to Be a Millionaire along with Joey McIntyre, Tyrese, Nick Lachey, and Lee Ann Womack. She dropped the $125,000 question and won $32,000 for her charity. After her death in 2002, the episode she appeared in was shown and was dedicated to her.

Lopes' funeral was held at New Birth Missionary Baptist Church in Lithonia, Georgia, on May 2, 2002. Thousands of people attended. Engraved upon her casket were the lyrics to her portion of "Waterfalls", stating "Dreams are hopeless aspirations, in hopes of coming true, believe in yourself, the rest is up to me and you." Lopes was buried at Hillandale Memorial Gardens in Lithonia.

In 2003, shortly after Lopes' death, her family started the Lisa Lopes Foundation, a charitable group dedicated to providing neglected and abandoned youth with the resources necessary to increase their quality of life. Her spiritual motto was the one that used for her foundation: "Energy never dies... it just transforms." Her foundation went into various underdeveloped villages and gave away brand new clothes to needy children and their families. In August 2007, the foundation hosted a charity auction, selling items donated by celebrities. It raised approximately $5,000 for the Hogar de Amor ("Home of Love"), an orphanage in Honduras. In 2012, the foundation began hosting an annual music festival, known as "Left Eye Music Fest", in Decatur, Georgia.

A documentary showing the final 27 days of Lopes' life, titled The Last Days of Left Eye, premiered at the Atlanta Film Festival in April 2007, for an audience that included many of Lopes' contemporaries, including Monica, Ronnie DeVoe, 112, Big Boi, India.Arie, and CeeLo Green. VH1 and VH1 Soul broadcast the documentary on May 19, 2007. Much of the footage was shot with a hand-held camera, often in the form of diary entries filmed by Lopes while on a 30-day spiritual retreat in Honduras with sister Reigndrop, brother Ronald and members of the R&B group Egypt. In these entries, she reflected on her personal life and career. A calmer side of her personality was on display, showing interests in numerology and yoga. She was in the process of setting up an educational center for Honduran children on 80 acres (32 ha) of land she owned called CAMP YAC, as well as another center called CREATIVE CASTLE.

In 2008, Lopes' family decided to work with producers at Surefire Music Group to create a posthumous album in her honor, Eye Legacy. Originally set to be released October 28, 2008, the release date was pushed back to November 11, then to January 27, 2009. The song 'Neva Will Eye Eva' and "Crank It", both features and was co-produced by Lopes' sister Reigndrop Lopes. The first official single from the album, "Let's Just Do It", was released on January 13, 2009 and features Missy Elliott and TLC. The second official single, "Block Party", features Lil Mama and Clyde McKnight. The album largely consists of reworked versions of tracks from the Supernova album. In November 2009, Forever... The EP was released which contained international bonus tracks not used on the Eye Legacy album. The EP was only available to download. An unreleased track featuring Lopes was uploaded to SoundCloud on the eve of the 10-year anniversary of her death by Block Starz Music. A portion of the proceeds from the song "Fantasies", which features Rapper Bootleg of The Dayton Family, will go to the Lisa Lopes Foundation.

At the age of 19, having heard of an open casting call for a new girl group through her then-boyfriend, Lopes moved to Atlanta to audition. Originally starting as a female trio called 2nd Nature, the group had been renamed TLC, derived from the first initials of its members at the time: Tionne, Lisa and Crystal. Things did not work out with Crystal Jones, and TLC's manager Perri "Pebbles" Reid brought in Damian Dame backup Dancer Rozonda Thomas as a third member of the group. To preserve the band's original name, Rozonda needed a name starting with C, and so became Chilli, a name chosen by Lopes. Bandmate Tionne Watkins became T-Boz, derived from the first letter of her first name and "Boz" (slang for "boss"). Lopes was renamed "Left Eye" after a compliment from a man who once told her he was attracted to her because of her left eye. Lopes emphasized her nickname by wearing a pair of glasses with the left lens covered with a condom, in keeping with the group's promotion of safe sex, wearing a black stripe under her left eye, and eventually getting her left eyebrow pierced.