The game, a home game for Jacksonville, is scheduled for Oct. 27, 2013, at Wembley Stadium. The Jaguars in August agreed to play one home game in London each season from 2013-16.
"Everyone associated with the Jacksonville Jaguars is very much looking forward to our four home games in London through 2016 and we're particularly thrilled and honored that our first opponent will be the San Francisco 49ers," Jaguars owner Shad Khan said Thursday.
It will be the second London game for San Francisco, which beat the Denver Broncos 24-16 in Wembley Stadium in 2010.
"The 49ers are excited and privileged to once again serve as ambassadors for the NFL and the game of football internationally," 49ers Chief Executive Officer Jed York said. "Our 2010 experience in London was tremendous. The atmosphere at Wembley Stadium on game day was electric.
"The ability for us to share 49ers football with our faithful fans internationally is a treat for everyone in our organization."
The 2012 edition of the NFL in London is set for Oct. 28 when the New England Patriots play the St. Louis Rams.