The result, with Venezuelan sides seldom expected to win matches let alone on the road, was the second successive surprise in Group Four after Catolica's 4-3 victory away to Velez Sarsfield of Argentina last week.
It left Caracas top of the group with six points, two more than Catolica after three matches. Velez and Union Espanola have played two matches and meet in Chile on Thursday.
"It's really pleasing to see the young players in our team playing so well in a competition as important as the Libertadores," Caracas coach Ceferino Bencomo said.
"Venezuelan football has progressed a lot... today, Venezuela and Caracas can play as equals against anyone," he told Fox Sports.
Striker Luis Cabezas scored twice for the Venezuelans in the 46th and 49th minutes. In between, their 23-year-old Panamanian midfielder Nelson Barahona drove the ball home from the rebound after keeper Cristopher Toselli parried a shot from Cabezas.
Pablo Calandria pulled one back in the 53rd but Catolica's misery was compounded by the dismissal of defender Hans Martinez 20 minutes from time for a second booking.
Estudiantes, coming back from a 5-0 roasting by Group Seven leaders Cruzeiro, came from behind to beat Guarani of Paraguay 2-1 in Asuncion for their second successive win.
After three matches, the Argentine side have six points, three less than the Brazilians. Deportes Tolima of Colombia are third with four points and Guarani bottom with none.
Striker Pablo Caballero put Guarani ahead with a penalty just before half-time but Estudiantes hit back with two goals in three minutes.
Midfielder Pablo Barrientos swept the ball in from a low left cross by winger Enzo Perez in the 50th minute for the equaliser.
Striker Leandro Gonzalez struck a sweet winner, right-footed from the left edge of the box that curled inside the far post with goalkeeper Pablo Aurrecochea getting a hand to the ball but failing to turn it round the post.
"We played poorly in the first half. The half-time talk from (coach) Eduardo (Berizzo) did us a lot of good, we played some good football early in the second half and then controlled the game," said defender Leandro Desabato, standing in as captain of Estudiantes for the injured Juan Sebastian Veron.
Five times champions Penarol, a dominant force in the earlier years of the competition first played in 1960, went top of Group Eight with a 1-0 home win over 2008 champions LDU Quito.
Atletico Junior of Colombia went top of Group Two with nine points after a 2-1 away win over Bolivia's Oriente Petrolero. All four teams in the group have now played three matches, Brazil's Gremio are second with six points, Leon de Huanuco of Peru have three and Petrolero none.
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