Italy forced into WC play-offs after stalemate
England only needed a point to be guaranteed of finishing top of Group I and booking its place in Qatar, but a win never looked in doubt, with Harry Maguire's header and Filippo Fabbri's own goal preceding a four-goal salvo from Kane.
The Tottenham striker became the first England player to score more than 12 goals in a calendar year with the first of two penalties, and by the end of the half he had gone from matching Jimmy Greaves' 44 international goals to drawing level with Gary Lineker (48) in third on the Three Lions' all-time scoring list.
Emile Smith Rowe marked his full debut with a goal before Dante Rossi saw red for San Marino, with Tyrone Mings, Tammy Abraham and Bukayo Saka compounding San Marino's misery in a non-competitive game.
Maguire scored the opening goal for the second game running when he headed Phil Foden's corner home, and in the 15th minute Saka's scuffed shot was inadvertently poked inside the near post by Fabbri.
Kane converted from the penalty spot after referee Rade Obrenovic penalised Rossi for handling Foden's acrobatic effort in the box, and the Tottenham striker doubled his tally with a volley from Smith Rowe's delivery.
Kane completed a 12-minute hat-trick by drilling another spot-kick – awarded after Alessandro D'Addario handled his header – into the top-left corner, and he made it four before half-time with a cool finish at the end of a mazy run.
Abraham was sent on as one of three half-time substitutes and teed up Smith Rowe in the 57th minute, with Mings looping a first England goal home after Rossi was shown a second yellow card for tripping debutant Conor Gallagher.
Jude Bellingham had a maiden England strike of his own chalked off following a VAR review two minutes later, but Abraham steered in a majestic half-volley and Saka nodded in a 10th to complete the scoring in the 79th minute.