A lot will be on the line on Saturday and Sunday with teams bidding to secure their post-season spots, including the Bills, who have a chance to claim the top seed in the American Football Conference (AFC)and a first-round bye.
But a complicated playoff puzzle has been made a little harder to piece together after the Bills and Cincinnati Bengals game last Monday was postponed when Hamlin collapsed making a tackle suffering a cardiac arrest.
Hamlin, who had to have his heartbeat restored on the field, spent most of the week on a ventilator in a Cincinnati hospital intensive care unit.
As the NFL enters the final weekend it is Hamlin, not Tom Brady, Aaron Rodgers or Patrick Mahomes, who has become the sport's most talked about player, with fans around the world rallying behind him.
The emotional rollercoaster the Bills have been riding will carry over into Sunday with the NFL planning a show of support for Hamlin with pre-game announcements at every stadium, his number "3" stencilled onto the field and players wearing "Love for Damar 3" sweaters during warmups.
The Bills have resumed preparing for the Patriots but general manager Brandon Beane conceded it is going to be far from business as usual as his players try to focus on the challenge ahead.
"It's going to be a celebration of life an ongoing life," Beane told reporters looking ahead to Sunday's game. "This is not only going to be a celebration of Buffalo but the whole country and internationally.
"The hair on the back of my neck is standing up right now thinking about it.
"It will be a challenge for our team to manage the emotions, there's going to be tears out there.
"That is probably going to be more of a challenge than the Xs and Os."
PLAYOFF RACE
While Hamlin and the Bills will be at the emotional centre of the weekend there is plenty of suspense up and down a full slate of games.
The playoff picture can quickly come into sharper focus on Saturday with Kansas City Chiefs able to lock up the coveted top seed with a win over the Las Vegas Raiders.
While a victory would earn the Chiefs a first-round bye it might not necessarily bring them home-field advantage.
In a special meeting on Friday, the NFL decided the AFC championship will be played at a neutral venue if the Bills or Bengals, who would have played one fewer game, reach the title contest.
Also on Saturday, the Jacksonville Jaguars host the Tennessee Titans in a winner-takes-all contest that will decide the top spot in the AFC South and a playoff berth.
The drama continues on Sunday with the resurgent Green Bay Packers, who started the season 4-8, hosting the Detroit Lions and can clinch a wildcard with a fifth straight win.
The Lions also need a win to keep their playoff chances alive but will need other results to go their way as well.
The New York Jets travel to Miami to take on the slumping Dolphins with both teams needing a win to remain in the playoff chase.
In the NFC the Philadelphia Eagles are expected to have injured quarterback Jalen Hurts back as they try to clinch the number one seed with a win or tie against the New York Giants.
If the Eagles lose, the San Francisco 49ers – winners of nine consecutive games – can secure top spot with a victory over the Arizona Cardinals.
Should the 49ers and Eagles both fall the Dallas Cowboys could snatch the NFC crown with a win over the Washington Commanders.
Follow all the action from the final round of the regular season with Flashscore.