Depay capitalised on a first-half error to score his first goal for the club after Juan Mata’s cross-cum-shot had put Louis van Gaal’s side deservedly in front.
Fatai Alashe pulled one back against the run of play before half-time, but Andreas Pereira made sure of the win for a much-changed United after the break.
Barcelona, who beat LA Galaxy, are the next opponents on Saturday, before a final match of the tour in Chicago against Paris Saint-Germain.
United – watched from the stands by former boss Sir Alex Ferguson – had a host of chances early on, but failed to find the back of net with any of them.
Summer signing Depay twisted and turned on the edge of the box before seeing a powerful strike well saved, with Wayne Rooney and Juan Mata unable to convert the rebound.
Rooney again failed to connect from a good position before United’s pressure told and Mata somewhat inadvertently gave United the lead with 32 minutes on the clock.
Picked out by the energetic Luke Shaw, Mata seemed to be aiming for the outstretched leg of Depay, but the ball evaded everyone and found its way into the net.
Soon it was two, as Depay this time definitely got the final touch, reacting to an awful backpass before slotting home on 37.
United looked to be cruising into the break with a two-goal lead, but after Morgan Schneiderlin was caught out on the touchline, Alashe (42) beat Phil Jones to the ball to put San Jose in with a chance.
Ten changes – goalkeeper Sam Johnstone, in for injured David de Gea, the only survivor – meant a young-looking United took time to adapt after the restart.
But, playing in a No 10 role, Brazilian youngster Pereira made sure of the result with a towering header from a Jesse Lingard cross in the 61st minute.
The hosts had some late pressure but it proved in vain as the 20-time top flight champions showed their 2015/16 season preparations are gathering pace.