Reyna returned to the USA squad this month for the first time since a bitter public spat with coach Gregg Berhalter stemming from last year's World Cup in Qatar.
And the Borussia Dortmund attacker slotted back into the team in style in Nashville on Tuesday as Berhalter's men ran riot against an outclassed Black Stars side.
Reyna opened the scoring at Geodis Park after just 10 minutes, sweeping home an emphatic finish after good work by Folarin Balogun down the right flank.
AC Milan's Christian Pulisic made it 2-0 from the penalty spot in the 19th minute after a clumsy challenge by Ghana defender Gideon Mensah upended Tim Weah in the box.
Pulisic made no mistake from the spot, rifling his shot down the middle as Ghana goalkeeper Abdul Manaf Nurudeen dived.
Balogun then made it 3-0 three minutes later after more good work from Weah.
The 23-year-old Juventus forward caught Jordan Ayew in possession and then crossed for Balogun, who turned away from his marker to rifle home a crisp finish.
The hosts added a fourth on 39 minutes from an indirect free-kick inside the Ghana penalty area.
Pulisic cleverly rolled the ball into Reyna's path and the forward shot high into the net for 4-0.
Berhalter rang the changes for the USA at half-time, removing Reyna, Balogun and Pulisic.
Unsurprisingly, the flurry of substitutions to so many key players affected the US fluency in attack, and they were unable to add to their tally in the second half.
