While regular season NFL games have been played at Wembley Stadium every year since 2007, the Jaguars are the only team committed to playing 'home' matches at the 90,000-seat venue on an annual basis.
The NFL said other teams could take games to continental Europe or Latin America if the Jaguars made a success of their foray across the Atlantic.
"We want to prove that fans here can become fans of a specific team," NFL Chief Marketing Officer Mark Waller said.
"If we can make this work here, there are many other markets," added Waller, a Briton.
European soccer clubs have made themselves more attractive to sponsors by building a global fanbase who follow their matches on television and online.
They have developed that following by going on pre-season tours around the world but have not taken regular league games away from their fans.
"The Premier League has led the way in terms of globalisation," Jaguars owner Shahid Khan said.
"Perhaps we can learn some lessons from them about how to spread the love for the NFL," he added.
The Jaguars have struggled to fill their roughly 67,000-seat home stadium at times and are one of the NFL's weaker franchises, having not posted a winning season since the 2007 campaign.
The 49ers were five-times Super Bowl winners in the 80s and 90s and are emerging as a force again in the NFC West. The game will be played on October 27, 2013.
The 49ers played at Wembley in 2010, defeating Denver Broncos 24-16 in front of a crowd of almost 84,000.
Wembley will host NFL action on Oct. 28 when the New England Patriots play the St Louis Rams, who are the designated home team.