Manningham, whose 38-yard catch helped set up the New York Giants decisive, last-minute touchdown in their 21-17 win over the Patriots in last season's Super Bowl, missed his second game with an injured right shoulder. He signed a two-year contract with the 49ers in the offseason.
For the Patriots, tight end Rob Gronkowski was inactive for the fourth game with a broken left forearm despite returning to practice on Friday.
Also inactive for New England were safety Derrick Martin, linebacker Tracy White, offensive lineman Marcus Zusevics and defensive linemen Jake Bequette and Ron Brace.
Missing the game for San Francisco were linebacker Tavares Gooden, safety Trenton Robinson, running back Jewel Hampton, guard Joe Looney and nose tackle Ian Williams.