Jose Valencia scored in the 23rd minute and James Rodriguez added another in the 90th, giving Colombia six points from two matches following a 4-1 opening victory over France.
The 42,000-strong sellout crowd produced non-stop noise with vuvuzelas - made infamous in the 2010 World Cup in South Africa - and exploding fireworks to welcome the team to the field. Colombia has emerged as a genuine contender for the title along with teams such as Spain, Brazil, Nigeria and six-time champion Argentina.
Colombia finishes up play in Group A against South Korea at Bogota on Friday, when Mali faces France in Cali. France and South Korea have three points apiece and Mali has lost its first two matches.
The top two teams in each of the six groups advance to the knockout stage and are joined by the top four third-place teams. The group stage ends Saturday.
Colombia has surely been helped by the thin air in the Colombia capital, which has an altitude of 2,600 meters (8,600 feet). Bogota is also the site of the Aug. 20 final.
Colombia dominated play in the first half and probably could have scored two or three with Rodriguez and Luis Muriel coming close.
The South Americans broke through when Valencia took a through ball, raced into the area and stepped around goalkeeper Cheick Sy. Mali defender Moussa Coulibaly stopped the first shot with his leg, but Valencia regained control and drilled the rebound into the net.
Rodriguez sealed the victory with a sizzling shot in the final minute. He ran to the far end of the field to celebrate and was swarmed by celebrating fans who ran onto the field briefly to mob him.
The home team got a break in the first half when Juan Cabezas picked up only a yellow card - lucky to avoid a red - for a reckless tackle from behind on midfielder Adama Toure.
Mali almost equalized in the 47th but Cheick Fantamady Diarra's rising shot was saved by Colombia keeper Cristian Bonilla. Diarra also tipped a cross wide several minutes later.
Colombia threatened late in the second half, but its attacks broke down as both teams began to tire.
Fabian Castillo had a great chance in the 74th but shot just wide from the left side.
Despite Colombia's edge in shots, Mali always looked dangerous on the counterattack.