What to watch for: There might not be any NFL playoff contenders in more desperate need of bounce-back performances than these two teams. The Saints have lost three straight for the first time since 2016 and need to get running back Alvin Kamara and their offensive tackles back from injury as soon as possible. Meanwhile, Bills MVP candidate QB Josh Allen has battled turnovers while Buffalo has lost two of its past three and fell out of first place in the AFC East. -- Mike Triplett
Bold prediction: Saints quarterback Trevor Siemian will throw at least two interceptions and complete less than 60% of his passes. He threw two interceptions in the loss to the Eagles last week and is averaging a 56.9% completion percentage on the season. The Bills' defense is ripe for a comeback game and has 15 interceptions on the season, tied for the second most in the NFL. Buffalo has also allowed opposing passers to complete just 57.7% of passes (lowest in the league). The Saints might be without Kamara and multiple other offensive players due to injuries, including tight end Adam Trautman, setting up the Bills' No. 1 pass defense for success. -- Alaina Getzenberg
Stat to know: The Bills entered Week 11 allowing the fewest points per game (15.0) and gave up 41 to the Colts. The Saints, meanwhile, entered last week ranked No. 1 in run defense (72.9 rushing yards allowed per game) before giving up 242 to the Eagles. Which defense will bounce back in Week 12?
Getzenberg's pick: Bills 27, Saints 20
Triplett's pick: Bills 23, Saints 22
Bills (-4) at Saints
MDS's take: Bills quarterback Josh Allen has not been playing well lately, but he'll certainly play better than Trevor Siemian, who is going to struggle mightily against a tough Bills defense.
MDS's pick: Bills 20, Saints 10.
Florio's take: It's another get-right game for the Bills, after another unexpected got-wrong performance.
Florio's pick: Bills 30, Saints 20.
The Saints are on a three-game losing streak, and Trevor Siemian is completing 57.3% of his passes in that losing streak. The Bills have averaged three turnovers lost per game the last three weeks, and if they don't clean that up this could be a close one, too. We're going to trust Josh Allen to right the ship in a tough game on the road. Buffalo is 2-3 ATS when favored by single digits, so this could be real close.
Pick: Bills 27, Saints 24
... That being said, the only rule I have that supersedes "Don't pick against the Saints at home on a holiday" is "always pick against Trevor Siemian." The Saints are 0-3 since Siemian took over as their starting quarterback and although I'm not going to pin the blame for those losses on him, I am going to pin most of the blame on him. If Alvin Kamara plays Thursday, I could see this being close, but if he's out, I think the Bills win by at least a touchdown.
The pick: Bills 31-24 over Saints
The Bills are due for a bounce-back game, and this game in New Orleans will be where Allen resumes his MVP campaign, and the Bills get back on track to being one of the top three elite teams in the AFC. There are now several games worth of film on Siemian, and the Bills will take advantage of Alvin Kamara's injury. — Andrew DeWitt, senior sports betting editor