Jefferson Montero, scorer of the second goal, was at the heart of Ecuador's best moves as they pulled the hosts apart to make it four wins in as many games in the single 10-team group.
Venezuela, who have never qualified for a World Cup, are bottom of the table after losing all four games.
After a lively start by the home side, Fidel Martinez had the ball in the net in the 10th minute for Ecuador, but his effort was ruled offside.
Martinez made no mistake five minutes later, however, racing through to drill past goalkeeper Alain Baroja after Venezuela lost possession in midfield.
Ecuador, who fell at the group stage in Brazil last year, struck the knockout blow in the 23rd when a clearance by Baroja, under no pressure, was intercepted by Miller Bolanos.
Bolanos fed Montero and the pair exchanged passes before Montero wrong-footed Baroja with a clever dummy and fired into the net.
Venezuela took control in the second half and created several openings but every time they lost the ball, Ecuador, who have already beaten Argentina away, looked like scoring.
Felipe Caicedo crowned Ecuador's performance when he met Montero's cross with a powerful, looping header from just inside the penalty area to score the third on the hour.
Walter Ayovi was denied a fourth when his 35-metre free kick crashed against the bar, before Josef Martinez side-footed home to reduce the arrears for Venezuela in the 84th minute.
(Writing by Brian Homewood; editing by Ken Ferris)
