Brett Lebda had a goal and an assist, and Pavel Datsyuk scored for Detroit, which broke the game open with three second-period goals.
The Red Wings have earned points in six straight (3-0-3) for a total of 108 to surpass Buffalo in the race for the President's Trophy, given to the team with the most regular season points.
Detroit, which has won five straight Central Division titles, also padded their division lead to three points over Nashville. Both teams have three games remaining.
Rick Nash scored his 25th with a wraparound for the Blue Jackets with just under a minute left, ending goaltender Dominik Hasek's bid for his 76th career shutout. He made 31 saves.
Columbus has lost three straight since a four-game winning streak.
After a scoreless first period, Detroit's special teams took over and staked the Red Wings to a 3-0 lead.
With the Red Wings on a power play early in the second period, Lebda snapped a shot from the right point at 1:57 that looked to handcuff goalie Fredrik Norrena, who had won four of his last five starts.
Seconds after another Detroit man advantage ended, the Red Wings retained puck possession in the Columbus zone and Holmstrom finished the play. He fended off defenceman Marc Methot and stuffed home a loose rebound at 10:27 while falling down to make it 2-0.
With Columbus trying to get back into the game on the power play, Datsyuk stripped the puck from defenceman Anders Eriksson and beat Norrena on a short-handed breakaway for his 27th at 17:16. Datsyuk has 38 points in his last 27 games.
Detroit easily killed all three Columbus power plays during the period and had two short-handed breakaways.
Holmstrom scored his 28th - one short of tying his career high - on a pingpong play near the Columbus net to make it 4-0 just 49 seconds into the third period.
Notes: Detroit captain and D Nicklas Lidstrom and LW Henrik Zetterberg did not play because of back injuries. ... Blue Jackets D Ole-Kristian Tollefsen injured his hip in the second period and did not return. ... The Red Wings can become the first team to finish first in the overall standings in three straight seasons since Montreal did it from 1976-78. ... A Detroit fan threw an octopus on the ice with just over two minutes left in the game.