The Italians largely dominated proceedings and had the match in their pockets once Goran Pandev and Samuel Eto'o had bagged goals in quickfire succession inside the opening 20 minutes at Zayed Sports City.
Frenchman Jonathan Biabiany slid home a third to add further gloss in the closing stages as Inter succeeded last year's winners Barcelona and added to Intercontinental Cup triumphs in 1964 and 1965 - a previous incarnation of the now expanded event.
Mazembe, from the Democratic Republic of Congo, had already made history by becoming the first African team to reach the final after a 2-0 upset win over Copa Libertadores champions Internacional of Brazil in the semi-finals - the biggest surprise in the 10-year history of the event.
But wily Inter proved a bridge too far as the experienced Italians struck early and then soaked up what limited and sporadic pressure the Africans were able to produce thereafter.
Inter had gone into the game hot favourites despite the injury absence of Dutch flier Wesley Sneijder - only the latest in a spate of injuries the Milanese have suffered this season, which had led to pressure on Inter coach Rafael Benitez as he attempts to replicate the success of the club last season under Jose Mourinho.
Adding the Club World Cup trophy to the Champions League, Serie A and Italian Cup titles masterminded by his predecessor will relieve some of that pressure on the former Liverpool boss as he looks to lift Inter in the second half of the season from their current seventh spot in Serie A.
Mazembe have become a major force in the African game on the back of five league title wins in the last decade and also the last two editions of the African Champions League.
But Inter proved a class above as Pandev fired home a neat left-footed poke after Eto'o had helped tee him up in the 13th minute.
Cameroon star Eto'o then claimed his own piece of the limelight as he drove in an instinctive right foot drive on the turn after Champions League final hero Diego Milito had combined with Esteban Cambiasso.
Milito should have made it three after beating the offside trap but drove his shot against the feet of onrushing keeper Muteba Kidiaba, who had earlier led the customary goalline pre-match prayer session for his teammates.
Brazilian defender Maicon went on the attack on the hour as Inter pressed for a third in style reminiscent of his World Cup goalscoring showing against North Korea - but could only hit the outside of the post as the Europeans continued to look comfortable.
Eto'o then tried to go it alone down the left rather than look for either substitute Stankovic or Milito but he ran into a forest of defenders and was hustled out of possession.
Again Inter came forward and Maicon whipped over a fine cross from the right in the 73rd minute but Pandev could not quite twist his head to make sufficient contact.
Inter had a brief but all too rare scare on 74 minutes when Dioko Kaluyituka went clear on goal but he lost his footing as he bore down on Inter keeper Julio Cesar, whom he tried to round but then knocked the ball too far before crumbling in a heap.
Biabiany, on for Milito, bundled home the third with five minutes to go after a Stankovic chip through the middle, to ensure that a European team would take the title for the fourth consecutive time.
Earlier, Internacional won the third-place play-off match 4-2 against South Korea's Seongnam Ilhwa.