True love steals away his character, Dr. John Carter, who reunites in the May 12 episode with girlfriend Kem (Thandie Newton), a health administrator he met doing volunteer medical work in Africa.
Carter leaves Chicago's County General Hospital in the May 19 season finale.
"It's very sad for me. Noah and I have a lot of history together," "ER" executive producer John Wells told USA Today. "He's a wonderful actor and a wonderful man, and it's been great to watch him grow up and get married and have a family."
In 2004, Wyle said he intended to leave "ER" when his contract ended this season.
"I've just got other stuff going in my life right now," Wyle told "E! News Live" last September. "I've got a son, I've got family and friends that said goodbye to me 12 years ago and are wondering when I'm coming back, and this little urge to scratch a different kind of itch in my career, and it's just coming to the end of the character's run."
When the series debuted in September 1994, Wyle played the impressionable young resident in a cast that included Anthony Edwards, George Clooney, Eriq La Salle, Julianna Margulies and Sherry Stringfield.
As they departed, Wyle turned into the show's centerpiece.
Stringfield returned to her role as Dr. Susan Lewis in 2001 after a five-year break.
The drama has been a durable performer for NBC, although it lost its No. 1 ratings status to newcomers including Fox's "American Idol." In head-to-head competition with CBS' "Without a Trace" at 10 p.m. EST Thursday, it trails in total viewers.