The goals came from the Tanzanian Mbwana Samatta and Ivory Coast's Roger Assale in front of their home fans in Lubumbashi.
The victory gave Mazembe a 4-1 triumph on aggregate, after the Congolese side had won 2-1 in the first leg in Algiers last weekend.
Samatta broke the deadlock in the 75th minute, putting Mazembe ahead from the penalty spot after a foul by Zinedine Ferhat on Roger Assale.
It was Samatta's seventh goal of the campaign, to leave him as the joint leading scorer of this year's African Champions League, alongside Bakry 'Al Medina' Babiker of Sudan's Al Merrikh.
Assale made sure of the victory with a goal four minutes into stoppage time, tapping in from close range after Samatta spearheaded a counter-attack.
Goalkeepers Muteba Kidiaba of Mazembe and Ismail Mansouri of USM were virtual spectators during the opening half of a match staged on an artificial surface.
The introduction of Assale and Ghanaian Daniel Nii Adjei for the second half bolstered the Mazembe attack and Malian Adama Traore shot wide from close range just past the hour.
But persistent pressure from the home team produced their two winning goals.
The north African side finished the game with 10 men after Zinedine Ferhat picked up a second booking.
Mazembe, managed by former Mali coach Patrice Carteron, clinched this trophy for the first time since 2010, when they crushed Esperance of Tunisia 6-1 overall.
They join Zamalek of Egypt as the second most successful sides in the tournament's history, behind eight-time champions Al Ahly of Egypt.
North African teams had dominated the African Champions League in recent years, with Algeria's Entente Setif winning last year's title.
But the first-leg deficit, and Mazembe's home advantage, meant it was an uphill struggle for USM Alger to stage a comeback.
Mazembe's success means they will now represent Africa at the Fifa Club World Cup next month in Japan.
TP Mazembe of the Democratic Republic of Congo were crowned club champions of Africa for a fifth time after a 2-0 victory over Algeria's USM Alger in the second leg of the Champions League final.