The procedure, a debridement of the ankle, will be performed by foot and ankle specialist Dr. Robert Anderson in Charlotte, N.C.
Manning suffered a high left ankle sprain in the Giants' 2013 season finale against the Washington Redskins and had been rehabbing the injury since.
"I went through the recovery and rehab after suffering the sprain," Manning said in a statement. "I was still experiencing some discomfort as I began my normal offseason preparation, and after consultation, we felt the right thing was to have Dr. Anderson clean out the ankle. The doc tells me I should be running in about six weeks.
"I'm looking forward to the start of the offseason program on the 21st. I will be in the weight room and in the meeting rooms so we can all learn the new offense. I got some good work in this week at Duke, and I think it's smart to get this procedure done now so the ankle isn't an ongoing issue. I'm eager to get to work with our new offensive coaches and system."
The Giants' offseason program starts on April 21 with two weeks of strength and conditioning and rehabilitation. They will then hold organized team activities (OTAs) May 28-30, June 2-3, June 5, June 9-10, June 12-13, and a mandatory minicamp June 17-19.
The 33-year-old Manning has started 151 regular-season games in a row for the Giants, most among active quarterbacks. He struggled in 2013, throwing 27 interceptions against only 18 touchdowns. He was sacked a career-worst 39 times.
Manning will be learning a new offense under new offensive coordinator Ben McAdoo.
The new Giants coaches on the offensive side of the ball are also quarterbacks coach Danny Langsdorf and running backs coach Craig Johnson. Sean Ryan and Kevin M. Gilbride have new assignments this season as Ryan will coach the wide receivers and Gilbride will oversee the tight ends. Ryan had served as quarterbacks coach and Gilbride the wide receivers coach the previous two seasons. Pat Flaherty remains as the offensive line coach.