The teams arrive in contrasting form; the Jaguars have lost their first seven games, conceding 222 points in the process, while the 49ers - who lost to Baltimore Ravens in last season's Super Bowl - are well placed at 5-2 and on a four-match winning streak.
To whet your appetite ahead of the latest London renewal, Sky Sports looks back over the previous seven regular-season games in the capital.
2007 - New York Giants 13-10 Miami Dolphins
The NFL's first regular-season game in Europe was a wet and wild affair between New York Giants and Miami Dolphins, two teams with a strong British following.
The turf cut up so badly underfoot as to make passing fraught with danger. Giants QB Eli Manning completed just eight-of-22 for 59 yards but did at least run in his side's only touchdown as they opened a 13-0 lead at half-time.
The Dolphins, who went on to finish with a 1-15 record in Cam Cameron's only season as head coach, came back in the second half, Ted Ginn Jr's touchdown reducing their deficit to three points with two minutes left to play.
But they did not get the ball back as the Giants closed out a win that proved the start of a renaissance, culminating in Super Bowl glory four months later.
2008 - San Diego Chargers 32-37 New Orleans Saints
Drew Brees wowed another full house with a passing masterclass as New Orleans Saints prevailed in a shootout over San Diego Chargers.
Brees connected on 30-of-41 for 339 passing yards and three touchdowns, including a 30-yarder to Lance Moore in the second quarter that prompted a celebration more often seen in the English Premier League - Moore sliding across the grass on his knees.
Chargers QB Philip Rivers topped Brees with 341 yards through the air and also produced three touchdowns - but could not quite engineer a fourth-quarter comeback.
Rivers hooked up with Vincent Jackson with just over two minutes remaining to put San Diego back within a score at 37-30.
But, despite twice getting the ball back in a frantic finale - which included Brees having to take a safety in his own end zone - Rivers' efforts were in vain as the game ended with his Hail Mary failing to find a team-mate.
2009 - New England Patriots 35-7 Tampa Bay Buccaneers
The third Wembley showdown was the most one-sided affair as New England Patriots rode Tom Brady's hot arm to a comprehensive success against Tampa Bay Buccaneers.
Brady, one of the standout quarterbacks of his - or any other - generation, piled up 308 passing yards and three touchdowns, although he was also picked off twice.
The contest was effectively settled early in the second quarter as, after New England safety Brandon Meriweather returned an interception to the house to end the opening series, Brady followed up with a couple of TD strikes.
Brady's favourite target Wes Welker finished with 10 catches for 107 yards, while the Patriots added a couple more touchdowns after half-time to ice the victory.
2010 - Denver Broncos 16-24 San Francisco 49ers
Troy Smith made the most of a rare start to lead a fourth-quarter comeback as San Francisco 49ers edged out Denver Broncos.
Quarterback Smith, preferred to namesake Alex, ran in one score himself and then found Michael Crabtree with a 28-yard touchdown pass as the 49ers came to life late in the game.
Denver back-up QB Tim Tebow had barrelled in from close range for the only touchdown of the opening three quarters before Matt Prater's field goal padded the Broncos' lead to 10-3 with just over 14 minutes left.
But Smith's heroics were supplemented by a third San Francisco touchdown in quick succession from running back Frank Gore - meaning Brandon Lloyd's late effort for the Broncos was immaterial.
2011 - Chicago Bears 24-18 Tampa Bay Buccaneers
Running back Matt Forte ran free as Chicago Bears claimed a 24-18 win over Tampa Bay Buccaneers.
Forte piled up 145 yards and a touchdown on 25 carries, enough to make up for a mixed display from Bears quarterback Jay Cutler who threw two interceptions and was under pressure all day.
Cutler's opposite number Josh Freeman also struggled when he went to the air and was picked off on four occasions.
The Bucs came into the game with a 4-2 record but the defeat was the start of a 10-match losing run that cost head coach Raheem Morris his job.
2012 - St Louis Rams 7-45 New England Patriots
Brady returned to produce another fine display, throwing four touchdown passes to lead New England Patriots' rout of St Louis Rams.
The Rams actually led 7-0 after Chris Givens scored the opening touchdown on a 50-yard pass from Sam Bradford less than three minutes into the game.
But thereafter it was all Brady, who served up two touchdowns each for Brandon Lloyd and Rob Gronkowski.
Shane Vereen and Stevan Ridley also punched in scores for the Patriots as things got very ugly, very quickly for Jeff Fisher's Rams.
2013 - Pittsburgh Steelers 27-34 Minnesota Vikings
On paper this wasn't the most promising match-up, both teams arriving in England with 0-3 records.
But they produced a fine spectacle with Vikings running back Adrian Peterson running in two scores to help his side build a 34-17 lead entering the final quarter.
The Steelers made things interesting when Ben Roethlisberger found Jerricho Cotchery with a 15-yard touchdown pass before a Shaun Suisham field goal made it a one-score game with more than three minutes left on the clock.
Roethlisberger got the ball back and took the Steelers on a 10-play, 72-yard drive before his fumble on third down at the Vikings' six-yard line sealed the result.