Following a scoreless second period, Johnny Oduya broke a 1-1 tie at 8:02 in the third and the top-seeded Blackhawks raised their tempo to pull away from the seventh-seeded Red Wings.
Marcus Kruger netted three minutes later before Patrick Sharp added his sixth goal of the play-offs on an empty-net shot in the last minute.
Chicago will look to stretch their lead in the best-of-seven series when they host Game Two at the United Center on Saturday.
In the opener, the Presidents' Trophy-winning Blackhawks imposed their will and outshot Detroit 42-21.
Jimmy Howard stopped 38 shots and Damien Brunner recorded a goal in the first for the Red Wings.
Detroit stunned the Anaheim Ducks in the first round where they captured a deciding Game Seven to advance to a much tougher task against Chicago, who has won the last eight meetings between the teams.
Sharp collected two assists and Marian Hossa also converted a power-play shot for the home side. Corey Crawford needed just 20 saves as the Blackhawks continue to thrive.
Chicago overpowered Minnesota in the first round, outscoring their opponents by a combined 17-7 in a four-game sweep.
- Ice Hockey
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- Red Wings
- Johnny Oduya
- Patrick Sharp