"The time has come after an incredible six years to move on to new challenges," Newton said in a statement.
Newton, known as "Mr. Las Vegas," said April 20 will be his last show at the Stardust.
The move wasn't a complete surprise. Newton has been playing a limited schedule at the hotel-casino, and has been occupied with other obligations, including a USO tour of Iraq and "The Entertainer," his reality show on E! Television Network.
Rob Stillwell, vice president of corporate communications for Boyd Gaming Corp., the Stardust's parent company, said the parting was amicable.
"We have a high regard for Wayne and what he has meant to so many of our guests," he said.
Newton, 63, didn't say where he will go after the Stardust. Speculation centered on the Hilton hotel-casino, where his television show was filmed.
A Hilton spokesman said he couldn't confirm whether Newton was moving to the nearby hotel-casino to join another famous crooner, Barry Manilow, who is booked there into 2006.
A message left Wednesday with Newton's publicist was not immediately returned.