McDonald was sent back to the VFL after kicking just one goal across the opening two rounds of the season.
But the premiership forward made the most of Ben Brown's absence on Sunday with four goals, 16 disposals, three contested marks and three score assists in his team's 19.12 (126) to 9.9 (63) victory in front of 42,458 fans.
Bayley Fritsch chipped in with three goals, while star midfielders Clayton Oliver (34 disposals, 10 clearances, 10 tackles) and Christian Petracca (29 possessions, three goals) put on a midfield masterclass
Brodie Grundy had a field day in the ruck on the way to 22 possessions, 33 hit outs and seven clearances.
McDonald's fourth goal was one of the highlights of the match, with the 30-year-old competing hard in a ruck contest in the middle of the ground before running forward to receive a handball and set sail from 52m.
"I was pumped for Tommy Mac today," Demons coach Simon Goodwin said.
"He wasn't in the best of form in the first couple of weeks and we sent him back to the VFL where he actually played a really dominant game at VFL level, and then he's come in today and done the same thing for us.
"He was pretty dominant in the air when he got his chances, and that's what we're looking for.
"It's a competitive team to be involved in and Tommy's gone back and proven why he wants to be an AFL player."
Demons defender Jake Lever went off in the last quarter with a minor ankle injury, but he's expected to be fit for Saturday's match against Essendon in Adelaide.
Michael Hibberd is in doubt after being subbed off with an achilles issue.
Sunday's win improved Melbourne's record to 3-1 and moved them into third on the ladder.
West Coast are now 1-3 and face another season of pain given their injury woes.
The Eagles made seven changes to their team following the injury carnage from last week's western derby, which claimed stars such as Liam Ryan, Jeremy McGovern, Luke Shuey and Jamie Cripps.
West Coast were so short on tall options in defence that returning midfielder Elliot Yeo was forced to play the role of key backman at times.
Tim Kelly tallied a game-high 36 disposals for West Coast to go with five clearances and two goals, while Oscar Allen kicked three goals.
Melbourne's lead was only 19 points late in the second quarter, but the visitors kicked seven of the next eight goals to break the contest wide open.
"They must have had 18-19 premiership players, and we were pretty young. So I think we'll learn a lot," Eagles coach Adam Simpson said.
"We were disappointed we didn't fight it out for the whole game, but we'll look at the good stuff and leverage off that."
9°C