Signed as a free agent in February, Cruz lined a solo shot into the left-field seats to put the Orioles ahead. He hit 27 homers last year with Texas during a season marred by a 50-game suspension from Major League Baseball in the Biogenesis drug scandal.
After missing two seasons recovering from knee surgery, Boston's Grady Sizemore marked his return from a 922-day absence with a second-inning single. He also hit his first home run since July 15, 2011.
Zach Britton (1-0) got the win with two scoreless innings of relief and Tommy Hunter worked the ninth for his first save. Lester (0-1) gave up two runs in seven innings.