The Demons killed off the contest with the first six goals and gave their percentage a healthy boost with Saturday night's 22.7 (139) to 7.7 (49) win at the MCG.
Comben, who has a history of left leg injuries, was hurt when he went for a mark in the opening quarter.
Play was held up for several minutes and significantly, the Seven Network opted against showing a replay of the gruesome incident.
Comben was hospitalised with a suspected broken leg.
Fellow North forward Callum Coleman-Jones also was forced from the game in the third term after coming off second-best in a marking contest with Demons defender Steven May.
Completing a disastrous night for the Roos, Tom Powell needed help from trainers as he went off with a leg injury in the last term.
It is North's biggest losing margin under new coach Alastair Clarkson, after they won their first two games, and also Melbourne's fourth 100-plus score this season.
The Dees kicked their highest score this season and were on track to their biggest winning margin against the Kangaroos, before North kicked the last three goals of the match.
Melbourne midfielder Clayton Oliver has three more Brownlow Medal votes with his 37 possessions, while Christian Petracca and Angus Brayshaw, in his 150th game, also shone.
Cameron Zurhaar kicked North's first goal late in the opening term and the Demons led by 44 at the first change.
The Kangaroos were ahead in clearances, but it didn't matter as Melbourne dominated general play.
It went from bad to worse for North at the start of the second term when Jaidyn Stephenson gave away a free kick for high contact.
He protested to Ray Chamberlain - the worst-possible option, given the umpires' no-nonsense persona.
Sure enough, Stephenson was hit with a 50m penalty and then another, with Chamberlain holding up his hand to the North forward as Trent Rivers kicked an easy goal.
The Demons continued their rampage, kicking five goals to one in the second term for a 66-point lead at the main break.
Alex Neal-Bullen was rewarded with a goal for an outstanding run-down tackle on an unsuspecting Luke McDonald late in the second quarter.
Zurhaar kicked three goals, while impressive North youngster Harry Sheezel and Aaron Hall had 30-possession games.
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