The third baseman absolutely crushed a two-run shot to left-center in one of baseball's biggest parks, giving the Nats a 2-0 lead with no outs in the first. Denard Span had drawn a leadoff walk from Padres right-hander Tyson Ross before scoring on Rendon's ninth homer.
That continues a power surge for Rendon, who has now homered in four of the last six games, hitting four during that stretch to nearly double his season total.
Now it's up to right-hander Tanner Roark to protect that modest margin.
Update: Roark has thrown one career complete-game shutout and at whose expense? The Padres.
Roark has picked up right where he left off from his April 26 blanking of San Diego, holding the Padres to one hit while striking out seven and walking none through four scoreless innings tonight at Petco Park.
The Nats starter has thrown 60 pitches, 41 for strikes, during his outstanding start to the contest, helping to keep Washington ahead 2-0.
Update II: The Nats rallied for four runs in the sixth to blow this one open, taking a 6-0 lead in San Diego.
Washington batted around in the inning, sending nine men to the plate and bringing the four runs home on two hits, two walks, an error and a hit batsmen.
Wilson Ramos made it 3-0 with a one-out ground-rule RBI double to right. Ian Desmond then walked to load the bases before Danny Espinosa was hit by a pitch on his left kneecap, bringing another run home.
Nate McLouth drove in the last two runs of the frame with a single to right.
Espinosa stayed in the game, but Rendon was removed after the inning. Before the contest, manager Matt Williams indicated there's a bug going around the clubhouse. Rendon also took a grounder off his hand.
The rally chased starter Tyson Ross, who entered the night with a 2.85 ERA. But he ended it with a 3.22 ERA after allowing six runs (five earned) on five hits and three walks in 5 1/3 innings. He struck out seven.
Roark continues to hold the woeful Padres offense down. He has now struck out nine, walked none and allowed just one hit over six scoreless innings. Roark likely has plenty of gas in the tank, having thrown 82 pitches (58 strikes) so far.
Update III: What a gem from Roark.
The right-hander has now tossed 17 consecutive scoreless innings against the Padres this season after getting through the eighth unscathed.
He allowed two hits in the eighth, and blanked San Diego on three hits over eight innings. Roark set a career-high with 11 strikeouts while walking none. His night is done after throwing 107 pitches.
Roark is the first Nats starter other than Strasburg to fan at least 10 since July 25, 2013.
The Nats lead 6-0 in the ninth.
Update IV: Roark snapped a personal three-game losing streak and improved to 4-4 with his gem against the Padres.
Over his last six starts, Roark has allowed eight runs in 40 2/3 innings for a fantastic 1.77 ERA. That has lowered his season ERA from 4.17 to 2.91.
Ross Detwiler pitched a scoreless ninth to complete the 6-0 win. The Nats scored their six runs on just six hits while committing two errors. The Padres finished with three hits, but had just one before the eighth.
Washington began its 10-game road trip with its fourth straight win and sixth in seven games, pushing the team's record to 31-28. The Nats are now 3-2 against the Padres this season, but have outscored them 26-9.