Once Caldas were stunned by strugglers La Equidad, conceding two second-half goals to lose 2-0 on Saturday.
While La Equidad climbed off the foot of the table, that result opened the door for Cali, who were 2-0 winners over lowly Fortaleza on Sunday.
Yerson Candelo and Carlos Rivas were on the scoresheet for Cali at the Estadio Olimpico Pascual Guerrero.
Cali are one point clear atop the table in the Clausura phase, while Once Caldas fell two points adrift in fourth position.
Behind Cali are Medellin, who accounted for Patriotas Boyaca 3-1.
A Javier Calle brace and Vladimir Marin's strike helped end Medellin's run of three consecutive defeats.
Santa Fe's entertaining 2-2 draw at 10-man Envigado was also enough for them to leapfrog Once Caldas into third on goal difference.
Envigado played 48 minutes with one man less following Carlos Ramirez's red card but they still salvaged a draw thanks to Victor Cortes' 77th-minute equaliser.
Atletico Nacional - fifth in the table - claimed back-to-back wins.
Nacional were inspired by Juan Angel's brace as they trumped lowly Uniautonoma 3-0 on the road.
Alianza Petrolera - level on points with Nacional - downed Aguilas Doradas 1-0.
Juan Caicedo bagged a hat-trick, while Hernan Hechalar chipped in with a brace as Atletico Huila came from behind to rout Deportes Tolima 5-1.
Millonarios' winless run continued, as they played out a goalless draw at home to Junior.
Boyaca Chico and Deportivo Pasto also drew 0-0.
