A native of Alexandria, Louisiana, Desselle-Reid graduated from Grambling State University, where she first became interested in theatre. In 1996, she appeared in Set it Off as Tanika. One of her most beloved performances came alongside Halle Berry as Mickey in the cult classic 1997 movie B*A*P*S. 

Just days before Deselle-Reid's passing, Berry posted an old video of the two, in costume, touring downtown Los Angeles between shots for the film. "I'm in total shock," Berry tweeted, with a gif of the two from the movie. "Completely heartbroken. Gonna need a minute."

Berry would later post an official statement on social media. "Natalie taught us love, joy and humor through her characters," she wrote. "She could never dim her light, and it was infectious. With her I laughed harder than I'd ever laughed before. She showed us it was ok to be goofy and funny while still being sincere and extraordinarily kind. She and I would hoot and holler over every BAPS tribute we came across, sending them back and forth to one another, overwhelmed that our on-screen friendship meant as much to you as it did to us. She was especially humbled by that, as am I."

Dessell-Reid would also star as Brandy's evil stepsister in Disney Channel's 1997 made-for-TV adaption of Cinderella. She also appeared in sitcoms like Yes, Dear, ER, and Tyler Perry's Eve. She also starred in Perry's Madea's Big Happy Family as Tammy.