The Jaguars, who have a deal to play one home game in London for four consecutive seasons beginning in 2013, will face the 49ers on Oct. 27, 2013.
"This is a unique and important opportunity for the Jaguars franchise, as well as for our fans and community," Jaguars owner Shad Khan said. "We can't wait to see our global vision for the Jaguars become reality next season."
"We think Jaguars-49ers is a matchup our fans will really enjoy and a great way to start a new era in the international development of our game," NFL commissioner Roger Goodell said.
Staging games is seen as the testing ground for the NFL's global push, although taking regular-season games to Asia has been ruled out because of the time difference.
"If we could do it (play games) in the UK there is no reason not to do it in Europe or Latin America," NFL chief marketing officer Mark Waller said. "It's an experiment if we can make it work, there are many other markets we can build the footprint."