He informed the Giants of his decision on Wednesday.
Solder cited family concerns, including his son's battle with cancer and his own bout with cancer. He also has a newborn son.
Solder's son Hudson, 5, was diagnosed with a rare Wilms tumor in both kidneys at a young age. Solder missed practices at times last year while his son underwent cancer treatments and checkups.
Solder, 32, is also a cancer survivor. He was diagnosed with testicular cancer during a routine physical prior to the 2014 season. He played that season for the New England Patriots.
Solder signed a four-year, $64 million contract with the Giants in 2018. He was set to earn $13 million and count $19.5 million against the salary cap this year.
Players considered high risk for COVID-19 can earn $350,000 and an accrued NFL season if they opt out. Players without risk can be fronted $150,000.
The Giants were aware that Solder might opt out this year. They had contingency plans in place, in part because they loaded up at tackle this offseason. Two of the Giants' first three picks in this year's draft were offensive tackles. They also signed veteran swing tackle Cameron Fleming as a free agent.
The Giants selected Andrew Thomas fourth overall out of the University of Georgia and followed that up with the selection of UConn's Matt Peart in the third round. Thomas is likely to take over now at left tackle for Solder.
The Giants were set to have an open competition this summer. That will not happen now, but they were understanding of Solder's decision.
"We have great respect for Nate as a person and player," general manager Dave Gettleman said. "When he called today, I told him it is faith, family and football. He is doing what's best for his family."
Solder was set to be reunited with head coach Joe Judge, who was an assistant in New England, where Solder spent his first seven NFL seasons.
"I spoke with Nate this morning," Judge said in a prepared statement. "We were together in New England, obviously, and he has always been a thoughtful, conscientious person. Ultimately, he made this decision because it is the right thing for him and his family. We support Nate and Lexi and their children (son) Hudson, (daughter) Charlie and (son) Emerson. Our concern is for their health and well-being."