The 31-year-old became the first player to score 50 goals for his country, finding the net twice in the second half to lift his overall tally to 51 before he was substituted by coach Juergen Klinsmann and left the field to thunderous applause.
Donovan had lost his place in Klinsmann's squad after taking a break from the game and missing key qualifiers in March, but was eager to return to the international scene with the CONCACAF Gold Cup tournament kicking off on Sunday and a chance to get back in the frame for next year's World Cup in Brazil.
"For me and I think for a lot of our guys, every game matters in a real way," Donovan told NBC television before the start of the match.
"Hopefully put yourself in a position to start in the Gold Cup and then from there hopefully a chance to be part of the World Cup qualifying team."
He certainly put himself in a good position as the United States outclassed Guatemala on a warm summer's evening, coming close to scoring in the 40th minute off a cross from DaMarcus Beasley but his attempt slid just wide of the right post.
Just two minutes later, forward Herculez Gomez opened the scoring with his sixth goal for the United States, hammering home a right-foot shot inside the near post after latching on to a drifting through ball from midfielder Jose Torres.
The cheers from the crowd were deafening after Donovan finally recorded his 50th goal when he converted from the penalty spot in the 55th minute, achieving the feat in his 145th match.
Forward Chris Wondolowski scored his first international goal in the 71st minute after being set up after a weaving run by Donovan, and just a minute later Donovan struck for a second time after a probing pass behind the Guatemala defense from midfielder Stuart Holden.
With the home team continuing to attack at every opportunity, defender Clarence Goodson (84th minute) and midfielder Alejandro Bedoya (88th) completed the rout.
"Nice to be back," a smiling Donovan said of his return to the US team. "It was a great night, great crowd, great atmosphere and it's nice to be ready and prepared for the Gold Cup for a lot of us.
"Wondo (Wondolowski) got his first goal, Bedoya got his first goal, and 50 for me. It was a really good night."
- Sports & Recreation