"As great as this show is, and as fun as it is, it's just not a challenge any more," she told the Hollywood Reporter.
The announcement comes just months after the show faced accusations it was a toxic place to work.
It led to three senior producers losing their jobs and DeGeneres opening the current season with an on-air apology.
The Ellen DeGeneres Show, which has aired since September 2003, will come to an end in 2022 after its 19th season.
The daily mix of comedy, interviews and human interest stories has been a US television staple, though ratings have declined in recent years.
"I was going to stop after season 16," DeGeneres said. "That was going to be my last season and they wanted to sign for four more years and I said I'd sign for maybe for one.
"They were saying there was no way to sign for one. 'We can't do that with the affiliates and the stations need more of a commitment.'
"So, we [settled] on three more years and I knew that would be my last. That was the plan all along."
DeGeneres' show broadcast its 3,000th edition last month, which its host admitted had been an "emotional" experience.
"It's going to be really hard on the last day, but I also know it's time," she continued. "I'm a creative person, and when you're a creative person you constantly need to be challenged."
The 63-year-old went on to say that last year's allegations that the show's workplace was "dominated by fear" had not been a factor in her decision to pull the plug.
"If I was quitting the show because of that, I wouldn't have come back this season," she said, while admitting it "destroyed" her to see "everything I stand for... attacked".
"It broke my heart when I learned that people here had anything other than a fantastic experience - that people were hurt in any way," she went on.
According to the Hollywood Reporter, DeGeneres told staff of her decision on Tuesday and is due to give an interview to fellow chat show host Oprah Winfrey on Thursday.
Her show has won more than 60 Daytime Emmy awards, the most recent coming when it was named outstanding entertainment talk show in 2020.
The Ellen Show regularly attracts A-list Hollywood guests and clips from the show often attract millions of views on YouTube.
"Although all good things must come to an end, you still have hope that truly great things never will," said Mike Darnell of show producer Warner Bros.
He said the show was a "phenomenon" that had become "the premiere destination for both superstars and incredible heartfelt human-interest stories".