As Dr. John Carter, a blueblood charmer, Wyle created a naive and sometimes comic figure who became an excellent doctor.
In recent years, Wyle was paired with actress Thandie Newtown (search), who plays Kem, a health administrator he met doing volunteer medical work in Africa.
In the finale, Carter joins Kem in Africa and does his final shift in the ER, where the usual chaos breaks out, even with Carter's goodbye party going on down the street.
Wyle, 33, the only original star who remained with the medical drama through its 11 years, will return for four episodes in each of the next two seasons. "ER" has been renewed through the 2007-08 season.
"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.
The New York Post and Associated Press contributed to this report.