David Backes, David Perron, Alexander Steen and B.J. Crombeen added goals for the Blues, who have won seven of eight. They came into the game in 10th place in the Western Conference, six points behind eighth-place Calgary.
Chris Mason lost his shutout with just under 6 minutes left when Jake Voracek scored on a jam shot off a pass from Derick Brassard.
The Blue Jackets were without two of their top three scorers. Captain and top scorer Rick Nash missed his third game in a row with a lower-body injury, and Kristian Huselius his third game in the last four because of an upper-body injury.
The Blues were 2 of 4 on the power play.
Mason finished with 24 saves.
Columbus trailed 4-1 and had a man advantage for 4 minutes late in the game. The Blue Jackets pulled goalie Steve Mason for the extra attacker, but Crombeen notched his sixth on a short-handed empty-netter.
After a scoreless first, the Blues took firm control by with three second-period goals.
McDonald, in the mix all night on checks and scoring chances, carried the puck from the short boards on the left wing all the way behind the net and then curled to the high slot before wristing a hard shot for his 21st.
The next two goals were almost identical — rising shots that beat Steve Mason high on the glove side.
Just 1:39 after McDonald's tally, Backes came down the right wing on a 3-on-1 rush and rocketed a shot for his 15th.
With a minute left in the period, from almost the same spot, Perron took a pass from Steen and put the puck above Mason's catcher for his 17th.
The Blues outshot the overmatched Blue Jackets 18-6 in the period.
Steen had a shot clank off the post early in the third. Seconds later, he got the puck back and found the net from the point to make it 4-0.
NOTES: Blues C Patrik Berglund had a career-best six-game points streak end. ... The Blue Jackets were playing the second of a four-game homestand. ... St. Louis has at least one power-play goal in its last seven games against Columbus. ... The Blue Jackets had won three of the previous four meetings this season. ... The Blues' 20 road wins are their most in 10 years.