Morales met with an ankle specialist in Colorado on Monday and, after consulting with Angels trainers and doctors, elected to undergo surgery to "clean up" scar tissue and bone cysts in the area of the ankle he fractured while celebrating a game-winning home run on May 29, 2010.
Angels orthopedist Lewis Yocum said that the recovery from such a procedure is at least six months.
The Angels were optimistic Morales would return in time for the start of this season, but his rehabilitation had included one setback after another.
"I knew there were going to be some issues along the way, but obviously I wasn't ready to have surgery again," Morales said through an interpreter. "But at this point, I think this is the best for everyone involved, to get me back at 100 percent."
Dr. Thomas Clanton, who has served as team physician for the Houston Rockets and Houston Texans, will perform the surgery in Vail, Colo., "as soon as possible," Angels general manager Tony Reagins said.
"Kendrys has worked as hard as anybody in coming back from a serious injury, and it hasn't worked," Yocum said.
Yocum said the surgeon might decide to put a bone graft into Morales' ankle, but won't know until the surgery is under way.
Morales' recovery has been one disappointment after the next for the Angels, who initially thought he might return in time to play at the end of last season. The first surgery, performed last June, proved to be more complicated than doctors thought it would be. They inserted six screws in the bone to repair the fracture.
"It has healed. We're dealing with the consequences of a major fracture, the secondary changes that occur," Yocum said. "The initial blow of when he hit the plate was a devastating force and that was just transmitted to the entire ankle."
Morales, 27, finished fifth in MVP balloting in 2009, when he belted 34 home runs and drove in 108 runs. He led the Angels with 11 homers and 39 RBIs at the time of his injury last season.
The Angels have replaced Morales with rookie Mark Trumbo, who entered Wednesday's game batting .270 with six home runs and a team-leading 17 RBIs.
Morales' slow comeback has affected the entire roster. Reagins didn't know whether he would have Morales in his cleanup spot this season, affecting his offseason personnel decisions.
"It's definitely a challenge for us," Reagins said. "Kendrys is a significant part of what we do in the middle of our lineup. I think our team has learned how to deal with his absence, and we have to move forward."
Even without Morales, their former cleanup hitter, the Angels lead the American League with a .271 batting average, though they rank seventh in home runs and sixth in runs scored. Entering Wednesday's games, the Angels were in first place in the AL West, leading the Oakland A's and Texas Rangers by two games.
The Angels lost their No. 5 hitter, Vernon Wells, to a strained groin during Monday night's game. Wells is on the 15-day disabled list and expected to miss at least three weeks.
"We've had adversity before and we'll have adversity again," Reagins said. "This is part of what we have to go through to get where we want to be."
Mark Saxon covers the Angels for ESPNLosAngeles.com. Information from The Associated Press was used in this report.