Collaros threw a 15-yard touchdown pass to Bakari Grant 1:24 into the game and helped mount a 20-7 lead before the starting pivot made way for Jeremiah Masoli with about six minutes left in the second quarter.
Ray Holley ran eight yards for a touchdown and Medlock was good on a pair of field goals from 49 and 19 yards before Collaros sat down.
Winnipeg running back Cameron Marshall scored on a one-yard run in the opening half in front of 24,344 fans at Investors Group Field.
Collaros completed 14-of-17 pass attempts, while Bombers starting quarterback Drew Willy played the entire first half and was 11 of 17 for 142 yards.
Medlock added field goals from 21 and 22 yards in the second half.
Paris Cotton ran two yards for Winnipeg's other touchdown at 1:04 of the fourth while the Tiger-Cats conceded a late safety.
Lirim Hajrullahu was wide on a 36-yard field-goal attempt for Winnipeg in the second quarter and missed a new 32-yard convert following Cotton's touchdown.
Masoli went 8-of-17 for 106 yards.
The Ticats, who left a number of starters at home, also beat Ottawa in the pre-season. Winnipeg had a victory over Toronto.
Hamilton opened the game with a 53-yard kickoff return by Tim Smith. A 28-yard catch by Andy Fantuz helped move the Ticats down the field until Grant caught his touchdown pass.
Winnipeg replied with a 38-yard kickoff return by Carlos Anderson, who hurt a knee on the play and didn't return. Clarence Denmark bolstered the drive with a 45-yard reception.
The Bombers then sputtered near the goal line before prevailing for their own touchdown.
Backup QB Robert Marve was stopped once from the two-yard line and again from the one before Hamilton took an offside penalty that kept Winnipeg's drive alive.
After being denied again from the one, Marve handed off to Marshall and he ran in for the one-yard score at 6:13 to tie the game 7-7.
Medlock's pair of field goals made it 13-7 at 2:28 of the second quarter.
The teams exchanged offside penalties before Holley sprinted eight yards into the end zone at 9:03 for the 20-7 gap.
Brian Brohm, Josh Portis and Marve relieved Willy in the second half.