In a low-key affair in front of a subdued crowd of 55,990 on Thursday, Roy Hodgson's men earned their second win from two Group E fixtures thanks to goals from Phil Jagielka, Wayne Rooney, Danny Welbeck, Andros Townsend and an Alex Della Valle own goal.
Ranked 208th in the world - the joint-lowest nation along with Bhutan - San Marino defended with 11 men behind the ball for large periods of the game, but the ploy failed to prevent them falling to a 60th consecutive defeat.
With just one professional in their ranks, San Marino held out for 25 minutes before Jagielka opened the scoring and Rooney added his 42nd England goal from the penalty spot.
Welbeck then tapped home four minutes after the break for his third of this qualifying campaign after scoring both goals in the 2-0 win over Switzerland last month.
Substitute Townsend added a fourth with 18 minutes to go before Della Valle turned Rooney's cross into his own net to complete the rout, the second time the defender has scored an own goal against England.
England made four changes from the Switzerland clash last time out. Three of those alterations were in defence, including a first start for Calum Chambers, while James Milner replaced Fabian Delph in midfield.
Rooney saw an early free-kick beaten away by Aldo Simoncini before Welbeck's goal-bound effort hit Jagielka and flew wide.
England captain Rooney tested Simoncini with another shot from distance in the 19th minute as the home side continued to probe and the goalkeeper was equal to Raheem Sterling's strike five minutes later.
San Marino's respite was brief, however, as from the resulting corner Simoncini fell over in coming to claim Milner's delivery and Jagielka headed into the empty net.
The visitors mustered their first shot on goal 10 minutes before half-time as Matteo Vitaioli fired wide of the left-hand upright from 25 yards.
Simoncini made an outstanding save shortly before the break, somehow clawing Welbeck's close-range effort over the crossbar, but once again England capitalised on the resulting corner.
As San Marino struggled to clear the ball, Andy Selva was penalised for a high foot on Rooney, who dispatched the spot-kick into the top-right corner.
Hodgson introduced Alex Oxlade-Chamberlain at half-time and the Arsenal man had an immediate impact, charging down a clearance before teeing up club team-mate Welbeck to convert from six yards.
Oxlade-Chamberlain went close twice in quick succession, shooting wide from 25 yards before Simoncini got down well to his right to keep out a glancing header.
Rooney was twice denied by Simoncini before Adam Lallana, another half-time substitute, thought he had scored his first England goal when Oxlade-Chamberlain's shot deflected off him and into the net in the 62nd minute.
After it seemed the goal had initially been given, the effort was ruled out for offside, although replays showed it was Chambers and not Lallana who was beyond the last man as the ball was struck.
Townsend cut in from the right and fired a low shot inside Simoncini's near post to make it 4-0 and Della Valle's unwitting deflection 12 minutes from time rounded off another heavy defeat for the visitors.
Late on, Townsend went close to a second when Cristian Brolli cleared his shot off the line as England continued to go in search of further goals against their beleaguered opponents.
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