Lopes contributed her own self-written raps to many of TLC's hit singles, including "Ain't 2 Proud 2 Beg", "What About Your Friends", "Hat 2 da Back", "No Scrubs", "Waterfalls", and "Girl Talk". She originally received the nickname "Left Eye" from a boyfriend who noticed that her left eye appeared slightly more little than her right. As a result, she was regularly seen with markings–ranging from eyepatches to eye black–under her left eye throughout her career.

TLC started off as a female trio called Second Nature. The group was renamed TLC — derived from the first initials of its then three members — Tionne, Lisa and Crystal. Things didn't work out with Crystal Jones, and TLC's manager Perri "Pebbles" Reid brought in her backup dancer, Rozonda Thomas, as a third member of the group. To keep the "initial" theme of the band's name, Rozonda needed a name starting with C, and so became Chilli, which was coined by Lopes. Band mate Tionne Watkins became T-Boz, while Lopes was renamed Left Eye. Lopes celebrated her nickname by wearing an eye patch–often a wrapped condom, in keeping with the groups promotion of safe sex–later evolving to a black stripe under the eye, and then an eyebrow ring in her left eyebrow.

The group appeared on the scene in 1992 with the album Ooooooohhh... On the TLC Tip. With three singles, it sold 6 million copies worldwide and TLC became a household name.[citation needed] 1994 saw the release of CrazySexyCool, which sold over 15 million copies worldwide and cemented TLC as one of the biggest female groups of all time.[citation needed] TLC's third album, FanMail, was released in 1999 and sold over 10 million copies worldwide.[citation needed] The album's title was a tribute to TLC's loyal fans and the sleeve contained the names of hundreds of fans as a "thank you" to supporters.

During the recording of FanMail, a public conflict began between the three members of the group. Lopes sent a message to Vibe magazine saying, "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".[citation needed] In turn, 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:

T-Boz and Chilli declined to take up the "Challenge," though Lopes always maintained it was a great idea. Things were heated between the ladies for some time, with Thomas speaking out against Lopes, calling her antics "selfish," "evil," and "heartless."

After Fanmail, Lopes began to expand her solo career. She became a featured rapper on several singles, including former Spice Girl Melanie C's "Never Be the Same Again", which went to #1 in 35 countries, including the UK. She was also featured on the first single from Donell Jones' second album, "U Know What's Up", and she sang "Space Cowboy" with *NSYNC on their 2000 album, No Strings Attached. Lopes also collaborated on "Gimme Some" by Toni Braxton from her 2000 release The Heat. In 2001 she appeared in two commercials for The Gap, one solo and the other with India.Arie, Liz Phair, and Sheryl Crow, where she was featured singing, instead of rapping.

Lopes was also the host of the short-lived MTV series, The Cut, a series on which a handful of would-be pop stars, rappers, and rock bands competed against each other and were judged. The show's winner, which ended up being a male-female rap duo, 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 so impressed Lopes and the show's three judges, that she scored a record deal as well. About nine months before her death, 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 from a $125,000 question and won $32,000 for charity.[citation needed] A year later, in 2002, the episode of her drop was shown and was dedicated to her.[citation needed]

Lopes created "Left Eye Productions" to discover new talent. She helped the R&B trio Blaque to secure a record deal with Columbia Records.[citation needed] Their self-titled debut album was executive-produced by Lopes, who also made a cameo appearance on the album and in their music video "I Do". Lopes was also developing another new band called Egypt. They worked on her second album under her new nickname, N.I.N.A, meaning New Identity Not Applicable.

Lopes spent much of her free time after the conclusion of TLC's first headlining tour supporting Fanmail recording her debut solo album, Supernova. It includes a song titled "A New Star is Born", which is dedicated to her late father. She told MTV News:

Other tracks covered personal issues, including her relationship with NFL football player Andre Rison. In 1994, Lopes famously burned down Rison's Atlanta mansion, resulting in the loss of all his possessions. Among the album's twelve tracks was also a posthumous duet with Tupac Shakur that was assembled from the large cache of unreleased recordings done prior to his murder in 1996. The unreleased song, "Left Pimpin", was sampled for the song "Quickie", which is featured on TLC's fourth album, 3D. Initially scheduled for release on a date to coincide with the tenth anniversary of her father's death, Arista Records decided to delay, then cancel the American release. The album was eventually released between 2001 and 2003 in various foreign territories.