The actress's character Lexie Grey was killed off in the eighth season finale after a dramatic plane crash.
Leigh explained that she had decided to quit the ABC drama months before the storyline was written.
"Earlier this year, I made the decision that season eight would be my last on Grey's Anatomy," she said in a statement via TVLine.
"I met with Shonda Rhimes and we worked together to give Lexie's story appropriate closure. I am very lucky to have worked with this amazing cast and crew for five seasons. My experience on Grey's Anatomy is something that I will treasure for the rest of my life."
She added: "I want to take this time to say thank you to the fans. Your unconditional love and support have made these last five years very special for me. I look forward to my next chapter and I hope you will continue to follow me on my journey."
Chyler Leigh appeared in Grey's Anatomy in 113 episodes from 2007-2012.
Grey's Anatomy exec Shonda Rhimes recently hinted that there may be more major character deaths following the plane crash in season nine.