The network said Wednesday that Chelsea Lately will conclude its seven-year run with an August 26 finale.
It's an earlier-than-expected departure for Handler, whose contract expires at the end of the year.
"I myself am more surprised than anyone that I was able to hold down a job for seven years, and it was a fantastic seven years," the 39-year-old comedian said in a statement. "I will always look back at my time on E! as most people look back at their time in college. I'm glad I went."
"We are very proud of Chelsea Lately's long-running success and the unique space that the series carved out in late night television," E! president Suzanne Kolb said. "Chelsea brought a distinct voice to late night with her acerbic wit and fearless commentary and we look forward to providing fans with a memorable send-off that lives up to that tradition."
Handler's exit has been in the works for months. Her manager, Irving Azoff, told The Hollywood Reporter in March that Handler wanted to leave when her contract was up.
"She hired me to figure out her life after E! We have at least seven suitors and many ideas," he said.
Handler, who has publicly described the network as a "sad, sad place to live," is reportedly working on a production deal with Netflix.