Two of San Diego's opponents -- the Mariners (23-37) and the Orioles (17-43) -- are in last place in their respective divisions.
The Blue Jays, the third AL team the Padres will see in this homestand, are 34-27 and in fourth place in the AL East.
Of course, all three teams will have to do without the designated hitter, which could give San Diego (34-25) an advantage.
"Yeah, the Blue Jays I don't think have ever come to San Diego," Padres manager Bud Black said on Thursday. "They got a bat taken out of their lineup, they have to play a National League style of game, but it still comes down to pitching, defense [and] timely hitting.
"The Blue Jays are playing well. The Mariners -- I think we've got [Cliff] Lee and [Felix] Hernandez -- they're always tough, but we're looking forward to getting back home."
The Padres split a day-night doubleheader in New York on Thursday to finish a 3-4 road trip against the Phillies and Mets.
Last month in Seattle, San Diego dropped the opening game of the series, though the club touched Lee for seven earned runs in 6 1/3 innings in a 15-8 loss. The Padres won the final two games of the series, 2-1 and 8-1.
"It's just nice to get back home," said San Diego pitcher Jon Garland. "We play really good baseball there, and it'll be nice to get back home, even though we'll be getting home late tonight, our bodies will have to adapt back, but it will just be nice to get back home regardless of who we're playing."
The Padres will conclude Interleague Play when they face Tampa Bay on the road for three games beginning on June 22.
Corey Brock is a reporter for MLB.com. This story was not subject to the approval of Major League Baseball or its clubs.