Anderson, who picked up his second shutout of the season, was especially sharp in the third period with the Sabres pressing for the tie as the Senators snapped a mini two-game slide.
Scoreless after the first period, the Senators had a number of great chances in the second but couldn't beat Miller until Karlsson moved in shorthanded and blasted a shot just over the Buffalo goalie's left pad at 15:20.
Karlsson, last season's Norris Trophy winner as the league's top defenseman, says he always looks to go on the attack while killing a penalty.
"I think when you're one man short you can even create some momentum there," said Karlsson following his sixth goal of the season. "It's going to be good for the team if you see an opportunity once in a while."
Miller made 29 saves in taking the loss for Buffalo.
"It's tough to give up a short-handed goal," Miller said. "I think we had two guys over backcheck and left the high guy ... I want to make a save for the boys at some point there (but then) it turns into a game where they can keep everything to the outside."
Condra then doubled the Ottawa lead 1:54 later, banging home a loose puck off a scramble in front of Miller's goal.
"You need one of those dirty ones to start the roll and hopefully I did that," Condra said. "Without (injured center Jason Spezza) everybody's got to chip in and we've got to do it the dirty way for other things to open up."
Daniel Alfredsson had a chance to open the scoring for the Senators on the power play prior to the two-goal barrage, but the Ottawa captain's one-timer missed the net with Miller at his mercy.
Buffalo had a chance to get back in the game midway through the third when Ottawa's Jim O'Brien went off for holding and Kyle Turris was whistled for high sticking to set up a two-man advantage for 14 seconds. But Anderson and the Senators penalty killers did the job against a Sabres power play that finished the night 0-for-4.
Ottawa's Jakob Silfverberg had a chance to stretch the Senators' lead to three on a power play later in the period, but Miller sprawled to make a diving save at the side of the Buffalo net.
The Sabres held a 13-7 shot advantage in the first period but couldn't solve Anderson.
Ottawa finished 0 for 8 on the power play.
Ottawa visits Pittsburgh on Wednesday, while Buffalo is home to Boston on Friday. ... Attendance at Scotiabank Place was 18,429.