Thomas was born in Atlanta, Georgia and graduated from Benjamin E. Mays High School in 1989. Her father, Abdul Ali, is of Arab and Indian descent and her mother, Ava Thomas, is of African American and Native American descent. Thomas, who had been raised by her mother, later allowed the Sally Jessy Raphael television talk show to air footage of her meeting her father for the first time in 1996.

Thomas was first a Dancer for Damian Dame. In 1991, she joined TLC, replacing founding member Crystal Jones, and was nicknamed "Chilli" by Lisa Lopes so that the group could retain the name TLC. The group went on to sell over 65 million records worldwide and became the best-selling American girl group of all-time; only the Spice Girls has sold more. Chilli has won four Grammy Awards for her work with TLC.

Thomas made guest appearances on television shows such as The Parkers, That 70s Show, Living Single and Strong Medicine. In 1992, she made a brief cameo in the video for "Jump" by Kriss Kross. In 2000, she was featured in the made-for-television movies A Diva's Christmas Carol, Love Song (with Monica), and in the film Snow Day. In 2001, she co-starred in the action film Ticker, directed by Albert Pyun and "House Party 3". She also played a small role in the 1998 film Hav Plenty. In 2011, Thomas made cameo appearances throughout the first season of VH1's Single Ladies. She appeared again on the show's second season performing her unreleased track, "Flirt," written by Tiyon "TC" Mack and produced by Soundz.

At age 20 Thomas became pregnant by Producer Dallas Austin, however due to career aspirations and the outside pressures, she aborted the pregnancy. On her show, What Chilli Wants, she would reveal having regretted the decision. Thomas and Austin continued their relationship, and would later have one son, Tron Austin (born June 2, 1997). In 2001, Thomas began dating Usher. Their relationship lasted for two years: they broke up in December 2003, followed by a media frenzy surrounding the personal nature of Usher's fourth album, Confessions. His fans inferred the reason he and Thomas split is due to infidelity on his part, giving allusions to the lyrics of the songs. In an interview on The Bert Show on the Atlanta radio channel Q100 on February 17, 2004, Thomas claimed that Usher cheated on her: "Usher did the ultimate no-no to me....I will never be with him again, and that is that". Usher defended: "...it just didn't work out. But cheating is not what caused the relationship to collide and crash. That ain't what broke it up".

Since the death of group member Lisa "Left Eye" Lopes in April 2002, Thomas and Tionne "T-Boz" Watkins have occasionally performed as a duo. In 2009, Thomas and Watkins performed a series of concerts in Asia.

Thomas and the rest of the members of TLC were big proponents of encouraging safe sex. For the music video of the song, "Ain't 2 Proud 2 Beg" Thomas and other band members wore condoms on their clothing. In 2003, Thomas and Watkins teamed up with Agouron Pharmaceuticals to create a national education program about HIV/AIDS. The program supplied people with information about HIV/AIDS, including prevention and treatment.

Thomas began working on her solo album in 2000 after the completion of promotion for TLC's third album, FanMail (1999). She ceased production when work began on the next TLC album, 3D (2002). In 2006, rumors of having signed a four-album deal with singer/rapper Akon's label Kon Live Distribution in 2006, she later denied these reports and confirmed that she was entertaining offers from other record labels. It was confirmed that the name of the album would be titled Bi-Polar, but due to scheduling conflicts and constant delays, the album was shelved. The album was once rumored to include work by Missy Elliott as well as tracks produced by T-Pain and Tricky Stewart. Certain tracks that were intended for the album were leaked from 2006 to 2008. A track titled "Gameproof," which featured her TLC bandmate T-Boz, was leaked in spring 2006. On February 16, 2007, "Straight Jack," a track featuring Missy Elliott and produced by Polow da Don was leaked. The track entered the Deutsche Black Chart in at #35. In early April 2008, Thomas's first official solo single, "Dumb, Dumb, Dumb" was released.

In June 2009, VH1 announced the airing of a reality TV series starring Thomas. The series, What Chilli Wants, which documents Thomas's quest to find love and manage her life with the help of love and relationship expert Tionna Tee Smalls, premiered on April 11, 2010. The second season of What Chilli Wants premiered on January 2, 2011.

In late 2011, VH1 announced plans to produce a biopic on TLC to air in 2013. Thomas and Watkins have signed on as producers. Actress and singer Keke Palmer portrayed Thomas in CrazySexyCool: The TLC Story.

In 2012, Thomas started a non-profit organization called Chilli's Crew. The organization is an Atlanta program targeted to help girls between the ages of 13-17 with self-esteem issues.

In 2013, Thomas took a stand against cyberbullying after her son Tron was a victim. The gossip site MediaTakeOut.com targeted Thomas's son because of his apparel and questioned his sexuality. In response, Thomas created a petition through change.org to get the article deleted from the site and to stop staff members from gossiping about minors entirely. In her petition, she described what cyberbullying is and statistics about some of the victims. The site ended up removing the article and issuing an apology to her son.

In 2016, it was announced she had joined the cast of the film Marshall which is a biopic on the life of Thurgood Marshall; she plays Zora Neale Hurston.