Guzman's blast in the third inning staked the Padres to a 4-0 lead, which they held until the seventh, when starter Casey Kelly (2-1) surrendered three runs.
That's when the San Diego relief corps took over. Brad Brach, Joe Thatcher and Dale Thayer combined to limit the Rockies to one hit over three innings and Luke Gregerson turned in a 1-2-3 ninth for his eighth save.
The Padres evened their three-game series with the win.
Colorado's Drew Pomeranz (1-9) lasted three innings, surrendering four runs on four hits.
Chris Nelson, Charlie Blackmon and DJ LeMahieu each drove in a run for the Rockies.