The Rockies took a 3-2 lead in the top of the ninth on Todd Helton's leadoff homer against Huston Street, but the Padres bounced back in the bottom half of the inning.
Chase Headley opened the San Diego ninth with a home run to tie it and Kyle Blanks drew a walk from Rex Brothers (2-1).
Alexi Amarista reached on a bunt single and a sacrifice by Ronny Cedeno moved the runners up to second and third. Nick Hundley was walked intentionally to load the bases and Guzman, batting for Street, singled to left to give the Padres a walkoff victory.
Street (2-4) picked up the win despite surrendering the homer in the top of the ninth.