The Padres' Japanese ace Darvish – who left the Dodgers after being criticized by Los Angeles fans following the team's 2017 World Series defeat – battled through five innings to secure the win at Dodger Stadium.
Machado, meanwhile, a member of the Dodgers' beaten 2018 World Series team, crushed a first-inning home run off Dodgers ace Clayton Kershaw to set the Padres on the way to a victory that leaves the best-of-five National League Division Series finely balanced heading into games three and four in San Diego.
Machado - booed relentlessly by Dodgers fans throughout - also drove in a double to score Kim Ha-Seong in the top of the third to tie the game at 2-2 after Freddie Freeman and Max Muncy had homered to give Los Angeles a 2-1 lead.
The Padres' Jake Cronenworth ground out to put San Diego 3-2 up soon after Machado's double only for Los Angeles to grab their third homer of the night when Trea Turner smashed a fly ball to left field.
The crucial passage of play came in the sixth inning when Jurickson Profar punished a costly fielding error by Turner to drive in a run for Cronenworth and a 4-3 lead that the Padres never relinquished.
San Diego reliever Robert Suarez brilliantly navigated his way out of a bases-loaded jam in the bottom of the seventh inning to leave three Dodgers baserunners stranded.
Cronenworth homered off Blake Treinen to give the Friars a 5-3 lead in the top of the eighth as the Padres bullpen held firm to close out the win.
Braves blunt Phillies
In Atlanta, the reigning World Series champion Braves secured a series-levelling 3-0 victory over the Philadelphia Phillies after a sixth-inning rally.
Phillies ace Zack Wheeler looked to be in control but finally succumbed to the Braves' offensive pressure in the bottom of the sixth when Matt Olson singled to right field to score Ronald Acuna Jr with Dansby Swanson scrambling to third base.
Swanson then scored off an Austin Riley single to put Atlanta 2-0 up and the Braves extended their lead soon afterwards when Travis d'Arnaud singled to centre field to bring home Olson.
Phillies manager Rob Thomson put a brave face on the defeat as the series heads back to Philadelphia on Friday.
"Obviously we want to win both of these games - we had an opportunity to," Thomson said.
"But to leave here with a split and go back home in front of a packed house of passionate people that I think they'll give our guys a little shot in the arm and I think it will be great.
"Friday is going to be electric at the ballpark."
Braves skipper Brian Snitker meanwhile backed his team to be ready for the raucous atmosphere in Philadelphia.
"I've been in Philly when it's crazy. When I was a third base coach, every game we played there was nuts," Snitker said.
"These guys are used to it. It's going to be I guess the so-called hostile environment, obviously. This whole year has been nuts here - I don't think it's anything that they haven't been exposed to."
