Cassel threw for 248 yards and two touchdowns in an interception-free performance that will heap further pressure on struggling starter Christian Ponder who missed the game with a rib injury.
"We're a good team when we don't turn the ball over and Matt did a perfect job in that area, made some nice throws so I'm very happy for him and what he was able to accomplish," Vikings head coach Leslie Frazer said.
Ponder had thrown five interceptions and only two touchdowns in the Vikings' first three games as the team, which made the playoffs last season, slumped to an 0-3 start.
The Vikings led for almost the entire game although the outcome was in doubt until the last few seconds when a fumble by Steelers quarterback Ben Roethlisberger ended a drive than could have taken the game into overtime.
Cassel connected with Greg Jennings for a 70-yard touchdown pass in the first quarter and found Jennings again in the third quarter for a 16-yard touchdown pass.
Adrian Peterson ran for 140 yards and two touchdowns for the Vikings.
The loss dropped the Steelers to 0-4 for the first time since 1968.
Roethlisberger completed 36 of 51 passes for 383 yards and one touchdown but was intercepted once and sacked five times in addition to his fumble.
The game attracted one of the highest attendances in the NFL so far this season with 83,518 fans at Wembley Stadium for the first of two regular season match-ups this year.
The NFL first played a regular season game at Wembley in 2007 and the annual fixture has attracted near-sellout crowds with an average attendance of more than 80,000.
This season for the first time there will be two games with the Jacksonville Jaguars hosting the San Francisco 49ers on October 27.
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