Hillis ran for 94 yards on 27 carries while Colt McCoy connected on 22-of-32 passes for 211 yards and was not picked off for the Browns (1-1), who rebounded after a loss to the Cincinnati Bengals in their opener.
Cleveland's defense held the Colts to just four field goals until a late touchdown with the outcome already decided.
Indianapolis (0-2) lost a second straight game to start a season for the first time since Manning's rookie year of 1998.
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