Buffalo was eliminated from postseason contention.
On a day that was supposed to focus on two of the NFL's most prolific quarterbacks, Holliday made the biggest impact from his defensive end position.
Slowed by injuries this season and with just one sack in seven games, Holliday dominated rookie tackle Mike Williams en route to a record-setting day.
Holliday broke Bryce Paup's club record of four sacks set on Sept. 15, 1991, against Tampa Bay. Ezra Johnson had five sacks against Detroit on Sept. 3, 1978, at Detroit, but the league did not begin officially counting sacks until four years later.
"I can't say enough about my teammates today," Holliday said. "We got great coverage from our d-backs all day long. They really made Bledsoe hold the ball. All the factors that help us defensive linemen get sacks were happening out there today and I'm just very fortunate."
Holliday's big game came one day after his 16-year-old cousin died of congenital heart defect. Holliday's cousin, Marcus Warren, died in Hilton Head, S.C., after collapsing during a high school basketball game
"I had a late night last night with my family, we really didn't get much sleep," Holliday said. "My little cousin (Marcus Warren), the next superstar, he died tragically last night, and all of this today was for him.
"God gave me the strength and no doubt he was up there helping. I just have to believe he was helping me. When I was out there everything was happening in slow-motion."
One of Holliday's sacks led to a fumble by Buffalo quarterback Drew Bledsoe in the fourth quarter, which helped set up Brett Favre's 11-yard touchdown pass to Donald Driver that gave Green Bay a 10-0 lead with 7:23 remaining.
In addition to losing two fumbles, Bledsoe was intercepted twice while completing 18 of 36 passes for 179 yards. Bledsoe had four of the Bills' six turnovers.
"They did a nice job against us," Bledsoe said. "They've got outstanding players over there, and they made a lot of plays. It was a tough day all around offensively. It was tough to throw the ball for either team and they also did a good job against us defensively."
"We didn't play well enough on offense to win the football game," Buffalo Coach Gregg Williams said. "You've got to score points and you've got to protect the football. We've done a good job all year protecting the football. Today we didn't."
Favre also struggled but was able to improve to 35-0 when the gametime temperature is 34 degrees or less at Lambeau Field. The three-time MVP completed 15 of 33 passes for 114 yards with one touchdown and two interceptions.
Ahman Green rushed for 116 yards for Green Bay, which won its third straight game, but will need a loss by either Philadelphia or Tampa Bay to garner a first-round playoff bye.
"It's a great accomplishment," said Green of going unbeaten at home. "Naturally our goal was to go undefeated on the road as well, but that's always tougher. Our main goal was to go undefeated at home and then make our opponents come here for the playoffs, to make it easier on us. We're one step closer to that, but we'll still need some help."
Travis Henry carried 20 times for just 46 yards for Buffalo (7-8).
With a game-time temperature of 25 degrees, there were plenty of mistakes to go around by both teams.
Favre got off to an inauspicious start, getting intercepted by cornerback Kevin Thomas on the third place from scrimmage. Thomas returned the ball 20 yards to the Green Bay nine, but the Bills could not take advantage.
On third and goal from the four, Bledsoe made an ill-advised pass over the middle that was intercepted by safety Darren Sharper. But the Packers lost their Pro Bowler with a right knee injury when a helmet hit his leg on the return of his league-leading seventh interception.
That was the start of the mistakes for Bledsoe and the Bills, who turned the ball over on three of their six first-half possessions. All of the turnovers occured in Green Bay territory.
Green Bay was not much better with a turnover and three punts on its first four possessions.
The Packers finally produced the game's first points in the second quarter, moving 37 yards in 10 plays. Favre put the Packers in position with a 20-yard completion over the middle to the Buffalo 29.
After the drive stalled at the 15, Ryan Longwell kicked a 33-yard field goal to give the Packers a 3-0 lead with 4:02 remaining before halftime.
Bledsoe, who was sacked six times, nearly gave the Packers a chance to increase the lead before the half when he was intercepted by linebacker Na'il Diggs at his own 45 with 23 seconds remaining.
Bledsoe, who completed just 11 of 33 passes for 107 yards in last week's win over San Diego, did not look anything like a Pro Bowler in the first half, during which he went five of 15 for 49 yards and two interceptions.