Cruz, who entered play as the American League leader in RBIs with 42, was hit by a pitch on the left hand from Rockies left-hander Kyle Freeland in the third inning. Boog Powell replaced Cruz when his cleanup spot in the order came back around in the fifth inning.
Segura, who began the day as the AL's leading hitter with a .344 batting average, was injured on an awkward slide into second base in the fourth inning.
Segura tried to tag up from first base on a fly to left field by Danny Valencia. Rockies third baseman Nolan Arenado took the cutoff throw and threw to second, where DJ LeMahieu tagged out Segura, who appeared to make a late slide, for an inning-ending double play.
After staying down for more than a minute, Segura was helped off the field by assistant athletic trainer Rob Nodine and first-base coach Casey Candaele.
The Mariners announced Segura was undergoing further examination on his right ankle.