Jeff Skinner also scored for Buffalo, and Owen Power, Zemgus Girgensons and JJ Peterka each had two assists. Ukko-Pekka Luukkonen made 28 saves and won his third straight start.
The Sabres had not practiced for a week. The Buffalo-area is recovering from a blizzard that killed at least 40 people.
Okposo ''is a guy that has embedded himself and his family in this community,'' Sabres coach Don Granato said. ''This is life and lots of people in life and death situations, lots of families, too many lost loved ones, too many felt the pain of this storm that went through, and to have a guy like (Okposo) that loves this community score three I felt was appropriate.''
Dominik Kubalik scored two goals for Detroit, which lost for the seventh time in nine games. Jordan Oesterle also scored, and Magnus Hellberg made 29 stops.
''You can't give them easy offense,'' Red Wings coach Derek Lalonde said. ''In the second, we literally had three pucks on our stick that ended up in the slot on their stick and that was just too easy for them.''
Buffalo grabbed control with four goals in the second period, opening a 5-0 lead. Okposo had two of the goals, beating Hellberg at 11:21 and 14:02.
Okposo sealed the win with an empty-net goal with 3:38 left, No. 6 on the season. It was the captain's first hat trick since Feb. 7, 2016, when he played for the New York Islanders.
''He's been here for me personally through my whole ride here and anytime we get to see him get rewarded like that and have a big night, it's awesome,'' Mittelstadt said.
Mittelstadt put Buffalo ahead to stay with 4:28 left in the first. He tapped the puck past Hellberg after a slap shot from Peterka went off the skate of Red Wings defenseman Jake Walman and right to Mittelstadt.
''I'm very happy for (Mittelstadt) to be rewarded,'' Granato said. ''There was timing and sense and feel and obviously finish that led to those (goals), and we needed that.''
Skinner made it 2-0 when he intercepted a pass from Filip Hronek and snapped in a shot for his 17th goal.
Kubalik got his goals 1:48 apart in the third period, the latter on the power play at 4:23. Oesterle cut the Sabres' lead to 5-3 at 7:11.
''Scoring always feels good but with the end result, it's not nice, so it's nothing to be happy about,'' Kubalik said.
Red Wings goalie Ville Husso did not dress against Buffalo because of an illness. Alex Nedeljkovic backed up Hellberg.
SABRES DEFENSE RESTORED
Sabres defensemen Power and Jacob Bryson returned to the lineup. Power missed the past three games after he sustained a lower-body injury in an off-ice pregame warmup activity Dec. 15. Bryson last played Dec. 13 and missed three games with a lower-body injury. To make room for Power, Buffalo placed defenseman Lawrence Pilut on waivers to send him to Rochester of the AHL.
Red Wings: Host Ottawa on Saturday.
Sabres: Visit Boston on Saturday.
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