Several key cast members, including Jennifer Esposito, Lauren Holly, Miguel Ferrer, Michael Weatherly, Pauley Perrette, Zoe McLellan, Cote de Pablo, and Mark Harmon, left NCIS for various reasons, such as creative decisions, health issues, or personal conflicts. These departures had a significant impact on the show, with some exits leaving fans shocked and disappointed. Each actor had their unique circumstances leading to their departure, contributing to the challenges faced by the series over the years.