The Barcelona man produced a brace while Jese also grabbed two goals before Luis Gil scored a late consolation.
Luis Gil had the only goal for the Americans, but it came after the team was already down four following a pair of braces from Jese and Gerard Deulofeu.
The U.S. joins Ghana without a result through the first match day of Group A. France defeated the African nation earlier in the day.
It couldn't have been as worse start for the U.S., as it was down within five minutes. Deulofeu was afforded far too much time to pick out a cross, and found a streaking Jese for a volleyed finish from close range.
The U.S. put together some decent attacking spells, but it all fell apart just before the break. First, Deulofeu struck in the 42nd minute with an absolutely sublime curling shot into the far post from the top of the box.
It went from bad to worse just two minutes later. Javier Manquillo produced some good work down the right flank, and was able to recover after a heavy touch to tee up Jese, who made no mistake for his second of the night, and Spain's third.
The U.S. back line was again carved open 15 minutes into the second half. Deulofeu was threaded in behind the defense and goalkeeper Cody Cropper made a poor decision to come way off his line, allowing the Barcelona man to round him and slot into an empty net.
The Americans did have a bright spot on the day in Gil, and the Real Salt Lake midfielder came though with a stunning left-footed shot from the top of the arc which found the upper corner to get his side a consolation.
The U.S. continues group play against France on Monday.