The former All-Pro selection underwent surgery for a torn pectoral muscle Tuesday, a league source told ESPNBoston.com, confirming an earlier report by Yahoo! Sports.
"He does a lot for us, on the field, off the field. We're just going to have to move on," coach Bill Belichick said Wednesday morning.
The Patriots re-signed defensive tackle Andre Neblett, who had been released last week, to fill Mayo's roster spot.
Mayo, a team captain, was injured in the fourth quarter of the Patriots' 30-27 victory against the New Orleans Saints on Sunday. He was spotted leaving Gillette Stadium with his right arm in a sling.
"That's always disappointing," said guard Logan Mankins, also a captain. "Jerod, he's a good guy, a good teammate, good player, so we're disappointed to lose him."
One of the few defenders in the Patriots' front seven who plays on all downs, the six-year veteran also had the important job of leading the team's defensive huddle, getting the play calls from the sideline and relaying them to teammates.
"When you lose someone like we did with Vince [Wilfork] or Jerod, it's tough," quarterback Tom Brady said. "But I'd say a lot of teams deal with it, too. You don't want to feel sorry for yourself and you realize that someone has to fill in and do the job.
Mayo is a two-time Pro Bowler and was a 2010 first-team All-Pro selection who led the Patriots in tackles in each of his first five seasons in the league. He has 55 tackles this season.
In the Patriots' base 4-3 defense, Mayo has mostly played the weak side, with Brandon Spikes in the middle and Dont'a Hightower on the strong side. Rookie Jamie Collins, the Patriots' top draft choice (52nd overall), is a leading candidate to step in for Mayo. Four-year veteran Dane Fletcher, whose primary contributions have come on special teams, is another option.
Meanwhile, Hightower said Wednesday that he will wear the communication device in his helmet and lead the Patriots' defensive huddle in Mayo's absence. As part of game-planning preparations for Sunday's road game against the New York Jets, Hightower has met with defensive coordinator Matt Patricia and linebackers coach Pepper Johnson about the added responsibility.
"I'm looking forward to it. It's definitely something that I knew down the road, if something ever happened, that I would have to step up and do it," he said. "I'm not nervous about it. It's something I've done before, maybe not in the NFL [but] I know everyone is behind me and they support me. That's all I can ask for."
The Patriots lost Wilfork, a defensive captain, to a season-ending torn Achilles on Sept. 29.
"As much as you hate to lose guys, there is nothing you can do about it and the season doesn't end," Brady said. "You have to keep fighting on, just as they would want us to, just like they did when I went out, just like they did when guys like Rodney [Harrison] went out.
"We've lost some key, critical guys over the years -- Ty Law got hurt one year. There have been a lot of guys who have been injured and you just have to try to fill the spot. Other guys have to pick up the slack. Hopefully our execution on offense is better; that would take some pressure off the defense, which has been playing great all year for us."