Cruz, who signed a four-year, $57 million deal after leading the Majors with 40 home runs last year for Baltimore, went 2-for-3 and took San Diego right-hander Ian Kennedy deep in the third with a two-run shot to left.
Cano, preparing for his second season with Seattle, went 2-for-3 with a double and two runs scored whle hitting in the No. 3 spot in front of Cruz as the Mariners started a lineup that looked close to a potential Opening Day nine.
Patrick Kivlehan, who had the game-winning RBI in Wednesday's 10th-inning win for Seattle, launched a three-run homer to left-center in the eighth, and San Diego second baseman Taylor Lindsey slugged a solo home run to center in the top of the ninth off Joe Saunders for the Padres' fourth run.
Seattle's starters put up six hits and three runs in the first three innings off Andrew Cashner and Kennedy. Cashner, last year's Opening Day starter for San Diego, allowed three hits and a run in his one scheduled frame while throwing 24 pitches.
Kennedy got the next two innings of work and surrendered three hits and two runs while throwing 46 pitches.
Seattle southpaw Roenis Elias, fighting for a spot as the No. 5 starter after winning 10 games last year as a rookie, threw two scoreless innings while allowing three hits and a walk. Elias benefitted from a pair of double plays in a 24-pitch outing.
Up next for Padres: The Padres face the White Sox at 12:05 p.m. PT at the Peoria Sports Complex as two of the top starters in the race for the No. 5 starter spot in the rotation -- right-handers Brandon Morrow and Odrisamer Despaigne -- make their Cactus League debuts. Manager Bud Black said earlier in camp that Morrow and Despaigne might have a slightest edge at this point on the other candidates in camp to win the final spot in the rotation, lefty Robbie Erlin and righty Matt Wisler. The game will be broadcast live on Gameday Audio.
Greg Johns is a reporter for MLB.com. Follow him on Twitter @GregJohnsMLB as well as his Mariners Musings blog. This story was not subject to the approval of Major League Baseball or its clubs.