Striker Pablo Mouche scored in the 51st minute to give six-times champions Boca their victory over 10-man Fluminense at La Bombonera on Thursday night.
Flu, who had defender Carlinhos sent off just past the half hour for a second booking for handball, were missing injured striker Fred and midfielder Deco and failed to repeat their 2-1 win at La Bombonera in the group stage.
Flu coach Abel Braga, angry at being denied a penalty for handball by Boca defender Facundo Roncaglia in the first half, told reporters: "They had two players more, the one we had one sent off and the referee."
Obolo headed past goalkeeper Rafael at the near post from left-back Emiliano Papa's cross.
Velez coach Ricardo Gareca, looking ahead to the second leg, said: "We had to win and not concede a goal, two fundamental things. With a team of Santos' standard nothing is certain whatever difference [in score] you take."
Wednesday's matches were draws with Universidad de Chile taking the upper hand against Libertad of Paraguay coming away from Asuncion with a 1-1 result.
