Ramirez was removed in the third inning when he fouled a ball off his left knee during an at-bat MLB.com reported.
Ramirez went down to the ground immediately and Cleveland manager Terry Francona quickly came out to check on the third baseman along with the training staff.
He then left the field on a medical cart a few minutes later.
The team announced that Ramirez had suffered a bruised knee and was going to have X-rays.
Two other Indians infielders are already on the injured list and will not be available for opening day.
Max Moroff, who has been getting more and more playing time with Cleveland due to injuries in the infield, came in the game for Ramirez to play third base.
Last season Ramirez led the team with 39 home runs, driving in a career-high 105 runs, hitting .270 in 157 games.
Ramirez has made the All-Star team the last two seasons, hitting a total of 68 homers with 188 RBIs for the Indians.
With both Kipnis and Lindor out, Moroff, Miller and Eric Stamets are in the mix to start the season at second base and shortstop for the defending American League Central champions.