Roy Hodgson's men, who have taken four points from their opening two games, will face a team ranked 207th in the world with only Turks and Caicos Islands sitting lower in FIFA's standings.
San Marino's only win came eight years ago when they shocked Lichetenstein 1-0 in a friendly.
Apart from that solitary victory the history books make grim reading for Giampaolo Mazza's side, who have lost 108 of their 114 matches.
Frank Lampard and Ryan Bertrand have withdrawn from the Three Lions squad through injury ahead of the encounter, while captain Steven Gerrard and Glen Johnson are suspended.
Meanwhile, the visitors have no new injury concerns for the game.
San Marino: LLLLLL
England: Hart; Walker, Jagielka, Lescott, Cole; Lennon, Carrick, Cleverley, Chamberlain; Rooney, Defoe
San Marino: A Simoncini; F Vitaoli, D Simoncini, Della Valle, Brolli; Matteo, Cervellini, Gasperoni, Marani, M Vitaoli; Rinaldi
Sports Mole says: 6-0