Milano collected the puck after Carolina's Sebastian Aho shot wide, racing to the other end to post his fourth goal of the season.
Milano, a left winger, earlier scored for the third game in a row, breaking scoreless tie midway through the third period. However, Jeff Skinner countered for the Hurricanes for his first goal of the season.
Columbus goalie Sergei Bobrovsky was within 85 seconds of recording his second shutout in as many outings until Skinner gloved a clearing attempt and then broke down the slot and scored an unassisted goal as the Hurricanes were using an extra skater.
Milano is the second player in franchise history to score goals in each of the team's first three games of a season. He matched the feat first accomplished by Kristian Huselius at the beginning of the 2010-11 season.
Milano, playing in only his 10th NHL game, scored with 9:59 remaining in the third, retrieving the puck from behind the net and delivering a shot that bounced off Carolina goalie Scott Darling's glove. Darling hadn't recovered enough to face the delivery.
Oliver Bjorkstrand, who sent in the initial shot, and Nick Foligno, who won the faceoff, picked up assists on Milano's goal.
Bobrovsky, who delivered a shutout to open the season against the New York Islanders, finished with 37 saves.
Carolina (1-0-1) was aiming for its first 2-0 start to a season since October 2010.
Darling made 25 stops for the Blue Jackets (2-1-0).
With an announced crowd of less than 8,000 in the building, it was up to the teams create energy and that seemed to happen only in small doses.
Darling, who was acquired in an offseason trade with the Chicago Blackhawks, got the start in both games of a season-opening home set before the Hurricanes head on the road.
Both teams had one power play in each of the first two periods, but the scoring chances were limited. Carolina won 27 of 40 faceoffs across the first 40 minutes, but the shots were even at 20 apiece.
The teams combined for at least five goals in each of their first three meetings last season.
NOTES: Blue Jackets RW Josh Anderson played in his first game after starting the season with a condition stint with Cleveland of the American Hockey League. He signed a three-year contract last week. ... Columbus C Zac Dalpe, who was scratched for the first time this season Tuesday night, began his career with the Hurricanes, playing in 41 Carolina games across three seasons, most recently in 2012-13. ... Hurricanes D Trevor van Riemsdyk, who made his Carolina debut Saturday night, was scratched. He was being evaluated for a concussion. ... Columbus next plays Friday night at home against the New York Rangers. ... The Hurricanes won't play another home game for two weeks, as they begin a four-game road stretch Saturday at Winnipeg.