Velez, Clausura champions in 2009, have 27 points from 13 matches with Godoy Cruz, who won 3-1 at Newell's Old Boys on Friday, second on 23. Olimpo, 2-1 winners at Huracan on Saturday, and River Plate are a point further back.
Right-back Fabian Cubero beat the offside trap to tap in a rare goal in the 38th minute and put Velez ahead. Substitute David Ramirez volleyed the second in added time.
"It was the moment to open a good lead over the rest," said midfielder Ricky Alvarez, who has been in superb form for Argentina's best club side.
"No, we're not tired, I think the will, humility and commitment of this team overcomes that," Alvarez told reporters when asked whether also playing the Libertadores Cup was taking a toll on Velez, who are in the quarter-finals of South America's elite club competition.
River had been expected to hold the lead for at least 24 hours but went down to a shock 2-0 home defeat by All Boys on Sunday a week ahead of the "superclasico" away to arch-rivals Boca Juniors.
Boca, recovering from a poor start to the championship, won 2-0 at Argentinos Juniors to extend their unbeaten run to four matches.
World Cup striker Martin Palermo, who had gone 10 matches without scoring, hit his third in as many matches to put Boca in front, stooping to head a rebound at knee height through the keeper's legs for another freak goal in his varied repertoire.
Boca climbed to 10th on 18 points with six matches to go in one of the tightest ever Argentine league championships.
They are ahead of Estudiantes on goal difference after the champions drew 0-0 at Lanus, their 10th match without a win in the league and Libertadores Cup from which they were eliminated by Paraguay's Cerro Porteno on penalties in the round of 16 last week.
