Alex Oxlade-Chamberlain had England's first strike on goal after three minutes, but Aldo Simoncini helped it on its way over the crossbar. Meanwhile, Simoncini just beat Theo Walcott to a long pass moments later – clattering the Arsenal man in the process.
Walcott was replaced by Aaron Lennon with 10 minutes on the clock as the home side continued to pen San Marino in their own half early on with Michael Carrick and Tom Cleverley both advancing from midfield.
The home side continued to dominate possession as the match approached the 20-minute mark, but a host of loose balls allowed San Marino the chance to clear their lines. However, they were unable to offer an attacking threat of their own.
Oxlade-Chamberlain had another effort for England after 25 minutes, but Simoncini was on hand to palm his effort clear of the danger zone. The home side's best chance of the half fell to Wayne Rooney just past the 30-minute mark, but his header was just wide of the target.
England twice struck the woodwork moments later through Carrick and Danny Welbeck, but they eventually had the lead after 34 minutes when Rooney converted from the penalty spot after Welbeck had been felled by Simoncini.
It was quickly two when Welbeck flicked a Lennon cross into the back of the net from close range. It might have been more in the latter stages of the half, but the score remained at two at the break.
England might have added their third early in the second period when Carrick combined with Rooney inside the penalty area, but his effort was deflected behind for a corner, before Gary Cahill missed from close range.
Cleverley was next to come close for the home side just before the 60-minute mark, but he could not make a proper connection as San Marino camped in their own box.
Rooney finally added the home side's third after 68 minutes when the Manchester United striker whipped a low effort into the far corner. Welbeck also grabbed his second from close range moments later.
Oxlade-Chamberlain made it five 13 minutes from time when he produced a cool finish from inside the area to add gloss to the scoreline on a strange night at Wembley.