After TLC's third album, Fanmail (1999), Lopes in 2000 became a featured rapper on several singles by other musicians, including former Spice Girl Melanie C's "Never Be The Same Again", which went to #1 in the UK charts and was #1 in 35 countries. They performed the song live on "Top Of The Pops" the week it went #1, which was Lisa's sole appearance on the UK show. It was co-written and produced by Rhett Lawrence. She also was featured on Donell Jones' debut single, "U Know What's Up", sang "Space Cowboy" with *NSYNC, a song from their 2000 album No Strings Attached and was featured on "Gimme Some" by Toni Braxton from her The Heat album published in 2000.

Lopes was also the host of the short-lived MTV series, The Cut, a precursor to American Idol in which a handful of would-be pop stars, rappers, and rock bands competed against each other and were judged. The show's final winner, which ended up being a male-female rap duo, was promised a record deal and MTV's funding to produce a music video, which would 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 herself a record deal anyway.

Lopes discovered the group Blaque and helped them obtain a record deal with Columbia Records. Their self-titled debut album was executive-produced by Lopes, who also made a cameo appearance on the album.

Lopes spent much of her free time after the conclusion of TLC's first headline tour behind Fanmail recording her first solo album, Supernova. Amongst the album's 12 tracks was 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 10th anniversary of her father's passing, Supernova was then delayed for two months before her American label chose to shelve the project. The album was released outside of the United States, and hardcore American TLC fans caused a demand for import copies of the album from the UK and Japan. Lopes then severed her solo deal with Arista (she remained contracted with the label as a member of TLC) and signed with Tha Row Records (the former Death Row label), intending to record a second solo album under the pseudonym N.I.N.A (New Identity Not Applicable).

Lopes was often plagued with controversy due to a rumored temper. She was arrested when she burned down the home of her boyfriend, former Atlanta Falcons wide receiver Andre Rison, in the early 1990s, after a major fight. Lopes, who was sentenced to 5 years probation and therapy at a halfway house, never was able to shake that incident from her reputation, and along with Lil' Kim, became one of hip hop music's bad girls. Along with her TLC band mates, Lopes filed for bankruptcy that same year claiming that poor royalties and an outstanding debt that was owed to Perri "Pebbles" Reid after she sued the group for breach of contract, caused them to take this action.

Lopes had already started work on both her second solo album and on songs for the fourth TLC album, 3D, when she died in a car crash in Honduras in April 2002. She had been there doing missionary work, which was something she had a passion for. It is said by those close to her that she had been undertaking a spiritual epiphany and had recently ended a month-long fast prior to her death. Her funeral was held at New Birth Missionary Baptist Church in Lithonia, Georgia. Lopes was interred at Hillandale Cemetery, also in Lithonia.