Kendrick christened the game with his seventh homer of his season, giving Washington a lead it never relinquished.
Grace was a late replacement for injured Matt Scherzer. The Nationals ace was waylaid by a sore neck and was placed on the disabled list before the game.
That left Grace to make his first start in the majors in his 61st appearance. His last start came in 2012 when he was pitching for Class A Potomac.
But Grace, a left-hander with a fastball-sinker mix, was tough against the Padres. He surrendered two hits and a walk with a strikeout in 52 pitches.
Joe Blanton (2-2), who pitched a scoreless sixth, got the win. Four other Washington pitchers combined to four-hit the Padres, with Sammy Solis getting the final three outs.
Luis Perdomo (6-8) lost for the third time in his last four starts. He worked six-plus innings and allowed five runs (three earned), six hits and three walks with five strikeouts.
The Nationals scored twice in the seventh inning on a pinch-hitter Alejandro De Aza's sacrifice fly and Kendrick's RBI single for a 5-1 cushion to end Perdomo's night.
Dusty Coleman's 415-foot solo shot in the fifth, which landed in the second deck, pulled the Padres within 2-1.
Grace was in a jam in the second after a leadoff single by Carlos Asuaje and a walk to Jose Pirela. But Grace got a double-play grounder from Yangervis Solarte and Wil Myers to fly out.
Washington forged ahead 2-0 in the second when San Diego got sloppy. Coleman's errant throw from shortstop on a force at second allowed Matt Wieters to come around and score.
Kendrick started the game with a homer for the sixth time this season as the Nationals took a 1-0 lead. He redirected Perdomo's 83 mph slider over the left-center field fence.
NOTES: Nationals manager Dusty Baker said RHP Stephen Strasburg will be activated off the disabled list and start Saturday. ... Nationals 1B Adam Lind was the lineup over Ryan Zimmerman, although Zimmerman entered in the seventh inning. ... Padres RF Hunter Renfroe was out of the lineup. Renfroe is scuffling, with his last home run coming July 25.