Goals from Nicolas Gonzalez and Angel Di Maria, both created by Rodrigo De Paul, also kept a packed Bombonera stadium enthralled in Buenos Aires for a match that had nothing riding on it.
Argentina have long qualified for the World Cup in Qatar later this year, while Venezuela were the first team in South America's single 10-nation qualification group to be eliminated.
The victory kept Argentina just four points behind group leaders Brazil with two matches to go.
Venezuela are now guaranteed to finish bottom after a 13th defeat in 17 qualifiers so far.
All four automatic qualification spots have been decided ahead of next week's qualification finale, with Uruguay and Ecuador booking their tickets to Qatar on Thursday night.
The only thing that remains undecided is who will finish fifth and head into an intercontinental qualification play-off.
Peru lead that battle by a point from Colombia and two ahead of Chile.
Argentina dominated from the off and opened the scoring 10 minutes before half-time as Gonzalez managed to stay onside to slide in De Paul's precise right wing cross from six yards.
Messi was heavily involved on his return, having been rested for Argentina's previous two qualifiers.
The veteran seven-time Ballon d'Or winner had three shots at goal from direct free-kicks but was unable to even test goalkeeper Wuilker Farinez.
Substitute Di Maria finally secured the victory 11 minutes from time when he ran onto De Paul's inch perfect ball from deep, before cutting inside onto his left foot and chipping the ball over Farinez and a back-peddling defender on the line.
Moments later, Di Maria turned provider, dinking the ball into the area where Messi arrived unmarked with time to control the ball on his chest before scuffing a shot home from six yards out.