USP, who reached the semi-finals of the competition last season under previous boss Glenn Tunbull, were playing their first game in this season's competition.
But they would fall at the first hurdle, with Frimley running out convincing winners.
Doubles from George Keenan and Jamie Hoppitt, along with Jordan Carter's strike, sent USP crashing to a heavy away defeat and out of the FA Vase.
Tom Grice's men did give themselves a glimmer of hope when leading scorer Joe Johnson pulled it back to 3-1 just two minutes after the restart.
But there were to be no Vase heroics this time around with US Portsmouth well beaten at Frimley.