Needing a draw from their last Group I qualifier to reach next year's tournament in Qatar, England went goal crazy on Monday as they scored 10 in a single game for the first time since a 1964 friendly against the United States.
England captain Kane took centre-stage after that, scoring four before the break to rewrite the record books.
Arsenal midfielder Emile Smith Rowe notched his first senior international goal in his maiden start.
Kane has scored 16 goals in 2021 for England, setting a calendar year record for the Three Lions as he surpassed the 12-goal tallies of George Hilsdon in 1908 and Dixie Dean in 1927.
The 28-year-old moved level with Gary Lineker on 48 England goals, with only Bobby Charlton (49) and Wayne Rooney (53) above him.
Kane is the first England player to score four times in a single game since Ian Wright against San Marino in 1993.
After bagging a hat-trick in Friday's 5-0 win over Albania, Kane is the first England player to score three or more in successive games since Tommy Taylor in 1957.
Southgate's men ended a memorable 2021 on a fitting high note after they reached the Euro 2020 final in July - missing out on a first trophy since 1966 in a painful penalty shoot-out against Italy.
Group winners England finished the qualifying campaign unbeaten in their 10 matches.
They will head to Qatar in 12 months established as one of the main contenders to win the World Cup.
San Marino famously scored after just eight seconds against England in a qualifier 28 years ago.
But there was never any danger of similar embarrassment for Southgate's team as they took the lead in the sixth minute against a woeful San Marino team bottom of FIFA's world rankings.
Phil Foden's corner reached Maguire and he rose highest to score with a powerful header, making it two goals in two games for the defender.
With San Marino completely out of their depth, England struck again in the 15th minute.
Maguire's pass found Saka, who cut in from the left-hand side of the San Marino area and drilled a low shot that deflected in off Fabbri's out-stretched boot.
Kane's goal-spree started in the 27th minute after Rossi put his hand up to get the slightest of touches on Foden's scissor kick, leading to a penalty that the Tottenham striker stroked in with ease.
England showed no mercy and Kane got his second in the 31st minute, guiding Smith Rowe's cross into the bottom corner.
Eight minutes later, Kane's header was blocked by Alessandro D'Addario's arm and he smashed the resulting spot-kick high into the top corner for his fifth England hat-trick.
Kane grabbed his fourth in the 42nd minute, weaving through the shambolic San Marino defence to slot home.
It was the first time England had scored six in the first half since 1946.
Smith Rowe got the seventh with a predatory finish in the 58th minute.
After Rossi's red card for tripping Conor Gallagher, Mings headed in Trent Alexander-Arnold's free-kick in the 69th minute.
Abraham made it nine in the 78th minute and, with England fans chanting "we want 10", Saka obliged with a close-range header 60 seconds later.
Standout matches today