A Ebenezer Assifuah double helped Ghana to their impressive win, which gives them a slim chance of qualifying for the next round.
Ghana started the game well and were comfortable in the opening half-hour, before eventually taking the lead through Frank Acheampong, who side-footed the ball past Cody Cropper after it fell to him in the penalty area.
Not long into the second period, they doubled their lead. Assifuah got his first of the game on the counter-attack after Daniel Garcia lost out in midfield.
USA gave themselves a lifeline when Shane O'Neill capitalised on some poor defending and finished well with 20 minutes to go.
Their hope diminished though, when Assifuah got his second, rising highest to head home a corner with just over 10 minutes to go.
Ghana then made sure of the victory in the final moments, with Kennedy Ashia running through and finishing well to make it 4-1.