His mound opponent is a former teammate making his debut for the lowly Philadelphia Phillies.
Locke has won all four previous starts versus the Phillies, who will give Kevin Correia the ball as they try to avoid an eighth straight road defeat in the opener of this three-game series.
It hasn't been a strong start to the season for Locke (3-3, 5.37 ERA), who has one win in his last nine outings and has been charged with 11 runs - 10 earned - over 10 1-3 innings in his last two. He gave up four runs over 6 1-3 innings Saturday as he did not get a decision in a 5-4 defeat at Atlanta.
Locke has a 3.52 ERA at home compared to 8.37 on the road. He has posted a 1.35 ERA against the Phillies, who average major league lows of 3.18 runs and 0.59 homers.
Players on Philadelphia's active roster are a combined 6 for 46 (.130) against him, including Ben Revere going 1 for 11 and Chase Utley with a double in six at-bats. Utley is hitless in 21 at-bats and has one of baseball's worst averages at .185.
Pittsburgh (32-27) will see a familiar face in Correia, who signed a one-year deal Monday with the Phillies. He takes the spot of right-hander Severino Gonzalez, who was 2-2 with an 8.69 ERA in five starts before being sent to the minors Sunday.
Correia pitched for San Francisco's Triple-A team in Sacramento this season, going 0-1 with a 3.58 ERA in six starts. He was released May 29 after exercising an opt-out provision in his contract, hoping another team would be willing to sign him as a starter.
"This is a good opportunity, but it's also a good city to play in," Correia said. "It's a great sports city to go play in. It's a place I've always looked at and I admire the organization and how things are run. So I'm happy to be here no matter what the situation is."
The right-hander will pitch at PNC Park for the first time since his two years with Pittsburgh from 2011-12, going 12-11 in each season.
He went 3-1 with a 3.77 ERA in five starts versus Pittsburgh between 2008-10. Pedro Alvarez is 3 for 5 against him while Andrew McCutchen is hitless in five at-bats.
Correia was tied for second in the majors with 17 losses in 2014 for Minnesota and the Los Angeles Dodgers.
Philadelphia (22-39) has lost 13 of 16 overall and is enduring its longest road slide since losing 11 in a row July 20-Aug. 11, 2013. The Phillies gave up four runs in the first inning in a second straight game in Wednesday's 5-2 loss at Cincinnati.
"It seems like the last couple of weeks, we've been trying to come from behind, playing catch-up in every game," manager Ryne Sandberg said.
Utley is hitting .151 off lefties and Ryan Howard is at .167.
Pittsburgh totaled three runs in dropping two of three to Milwaukee, avoiding a sweep with Wednesday's 2-0 victory. The Pirates were 3 for 24 with runners in scoring position in the series.
Alvarez homered Wednesday for the first time in 15 games. He has one of baseball's lowest line drive percentages at 16.3.
These teams split four games in Philadelphia from May 11-14.