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.
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.
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.
