Colorado has won five of its last six games and improved to 2-1-0 on its five-game trip. The Avalanche won in Ottawa for the first time since Feb. 11, 2016.
Valeri Nichushkin, Matt Nieto and J.T. Compher also scored for Colorado. Philipp Grubauer made 25 saves.
Brady Tkachuk scored the lone goal for the Senators. Marcus Hogberg stopped 30 shots.
Ottawa struggled from the start and didn't register its first shot until the 18:41 mark of the first period.
''Not ready to play,'' Ottawa defenseman Dylan DeMelo said. ''It's as simple as that. Not engaged, not detailed. The first 10 minutes of the game, we should probably shoot some pucks on net. When we did that, we had some O-zone time and caused some chaos.''
Ottawa has just two wins since Dec. 23 (2-7-7) and is 1-5-5 in its last 11 on home ice.
Compher rounded out the scoring early in the third as he beat Hogberg short side.
Colorado regained the lead early in the second as Niemo buried a one-timer off the rush. Makar then made it 3-1 with a blast from the blue line for his 12th of the season.
The Senators didn't register their first shot of the game until 18:41 of the first period, but still managed to get out of the period tied 1-1.
Colorado opened the scoring at the seven-minute mark after a defensive breakdown by the Senators left Nichushkin all alone in the right circle, before he fooled Hogberg with a wrist shot.
''We had a good start,'' Colorado's Nathan MacKinnon said. ''I thought we deserved a few more than one in the first. A lot of guys had good games.''
Ottawa finally registered its first shot of the game on its second power play of the night as Tkachuk fired a shot at Grubauer, which earned a cheer from the crowd. Less than a minute later, Tkachuk broke in alone and beat Grubauer glove side to tie the game on Ottawa's third shot.
''We played harder towards the end of the period,'' Senators coach D.J. Smith said. ''You saw (Tkachuk) kind of drag some of our guys into that, but they're too skilled to give that lead to them and when they made it 3-1, they just closed it down for us.''
DeMelo said many of Ottawa's problems should be easy to solve.
''The things that we could control, we're not doing that,'' he said. ''We can control shooting the puck, we can control going through guys and being engaged. If they make some good plays and score you kind of tip your hat to them, but it's things we can control and we can get better at.''
NOTES: Ottawa's Nick Paul returned to the lineup for the first time since suffering a lower-body injury on Jan. 7.
Avalanche: At Columbus on Saturday.
Senators: At Winnipeg on Saturday.
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