The victory will send Rafael Dudamel's side into the Copa America full of confidence.
West Bromwich Albion striker Rondon, who has been linked with a transfer away from the Baggies in recent weeks, put himself very much in the shop window with a match-winning display in which he also provided an assist for Jefferson Savarino to score Venezuela's second as a sorry United States side was torn apart.
United States coach Gregg Berhalter saw his players lose the first game of his time in charge three days earlier when they slipped to a 1-0 defeat to Jamaica and will have been concerned by a defensive horror show in which they conceded three goals inside 20 first-half minutes.
Venezuela's opener came courtesy of calamitous United States defending as goalkeeper Zack Steffen gifted a clearance to Yangel Herrera who fed Jhon Murillo and he laid the ball back to Rondon for a bundled shot into the net.
It was Rondon's flicked header that allowed Savarino to go through on goal moments later, the Real Salt Lake winger scoring at the second time of asking after his first shot came back off the post.
Rondon timed a run superbly on 36 minutes and brought Tomas Rincon's long ball under control before composing himself and rattling a left-footed shot into the corner of the net, beating Steffen at his near post from close range.
The hosts failed to improve after half-time, mustering just four shots across the course of the game, and Berhalter will demand better when they take on Guyana in the CONCACAF Gold Cup in less than two weeks' time.
Meanwhile, Venezuela will go into its Copa America opener against Peru on Sunday (AEST) in high spirits after an historic win and an unforgettable night for its in-form striker.