Cain struck out 11 and permitted just a single runner. McDonald, a career .069 hitter coming into the game, hit a sharp single to left field with two outs in the sixth inning.
Cain (1-0) pitched his third career one-hitter, his fifth shutout and 14th complete game.
Aubrey Huff homered as the Giants returned from a 2-4 road trip. Buster Posey hit an RBI double in his first regular-season game at AT&T since his season-ending collision at the plate with the Marlins' Scott Cousins last May 25.
McDonald produced his seventh career hit but Pittsburgh dropped its fourth straight game after being swept at Dodger Stadium. McDonald (0-1) allowed three runs on six hits in 5 2-3 innings, struck out one and walked three.
In Los Angeles, Aaron Harang set a Dodgers record with nine consecutive strikeouts, one short of the major league mark, and Los Angeles beat San Diego on four straight walks in the bottom of the ninth inning.
Matt Kemp hit a two-run homer and Harang tied his career high with 13 strikeouts in 6 1-3 innings to help the Dodgers win their fourth in a row. They lead the majors with a 7-1 record, their best start since 1981 when they opened 9-1 and went on to win the World Series.
Chase Headley hit a tying, two-run homer with two outs in the ninth off Kenley Jansen (2-0).
Andrew Cashner (0-1) retired his first two batters in the bottom half before walking Mark Ellis, Kemp and James Loney. Joe Thatcher came in and walked Andre Ethier on four pitches to force in the winning run.
In Washington, Jayson Werth hit a bases-loaded single off closer Sean Marshall in the bottom of the 13th to lift Washington over Cincinnati - the Nationals' fourth win in a row.
The NL East-leading Nats improved to 6-2, their best start since moving from Montreal to Washington in 2005.
After Marshall (0-1) got the first batter of the 13th on a groundout, Danny Espinosa reached with a broken-bat infield single. Ryan Zimmerman and Adam LaRoche then walked.
In St. Louis Ian Stewart hit a three-run homer, Bryan LaHair connected for a grand slam and Chicago hammered Adam Wainwright to spoil the St. Louis home opener.
Starlin Castro had three hits and a walk for the Cubs, who have scored 17 runs the last two games after totaling just 19 in the first six.
Wainwright (0-2) gave up eight earned runs - matching a career worst - on seven hits in three innings of work. He walked two and struck out three.
In Philadelphia, R.A. Dickey threw seven sharp innings and Jason Bay hit a two-run homer to help New York beat Philadelphia left-hander Cliff Lee.
Scott Hairston also homered for the surprising Mets, who are off to a 5-2 start.
Freddy Galvis hit his first major league homer for the Phillies. The five-time defending NL East champs are 3-4.
In Miami, Gaby Sanchez doubled in the 11th inning to score Chris Coghlan from first base and lift Miami over Houston.
Coghlan started the 11th with a sharp single that deflected off pitcher Brandon Lyon (0-1) for an infield hit before Sanchez pulled an 0-2 pitch that hit off the fence in left.
Ryan Webb (1-0) pitched a perfect 11th for the win.
The game was the Marlins' first at home since manager Ozzie Guillen began serving a five-game suspension for praising Cuban dictator Fidel Castro.
In Atlanta, Brian McCann had four hits, including a homer and four RBIs, and Dan Uggla's broken-bat single in the eighth gave Atlanta the win over Milwaukee in its home opener.
A three-run homer by McCann highlighted a six-run fifth that put the Braves up 8-3. Milwaukee rallied, tying it on Corey Hart's homer in the eighth.
Uggla hit a slow roller through a drawn-in infield to score two runs, snapping an 8-8 tie.
In Denver, Todd Helton drove in three runs, including a tiebreaking double in the eighth inning, to rally Colorado past Arizona.
Carlos Gonzalez singled with one out in the eighth off Bryan Shaw, whose pickoff attempt scooted past first baseman Paul Goldschmidt for a two-base error on Goldschmidt.
Shaw (0-1) struck out Troy Tulowitzki, who had three hits, but Helton stroked a cutter into the left-field corner.
That made a winner of Rex Brothers (1-1), who pitched a scoreless eighth. Rafael Betancourt got three outs for his second save.
