It’s time to lock in for our NFL Week 4 matchups. With three weeks officially in the books, we’re finally getting a clearer picture of who is a pretender and who is a contender.
Week 4 is shaping up to be a good, with shifting QBs across the NFL; we get the return of both Justin Fields and Brock Purdy, but the loss of Jayden Daniels and the sudden benching of Russell Wilson, giving rookie Jaxson Dart his first start.
Below, we'll give you our best NFL Week 4 predictions in the PrizePicks NFL cheat sheet — your ultimate resource for the top NFL picks for PrizePicks, projections to target, and matchup insights this week.
Just go to the PrizePicks NFL board, pick your players, and predict if they’ll have More or Less than their projected stats to win real money on all of the Week 4 action.
Let's get into all of our Week 4 predictions to target in the top matchups of the week for RB, WR, TE
Top RB Matchups & Predictions: Week 4
Bills RB James Cook vs. Saints
The Bills get a cakewalk matchup vs. the Saints team that hasn't won a game yet. That sets up well for the potential game flow and RB James Cooks workload here.
Cook has become a workhorse for the Bills, with 22 touches per game, 53 rushes (eighth in the league), and 284 yards (second) in three games.
He's also sixth in the NFL in rushing snaps, per PFF. His 4 rush TDs are a league best, and he's scored a touchdown in seven straight games.
Cook ranks 10th in the NFL among RBs in forced missed tackles, while the Saints rank fifth in missed tackle rate so far this season.
Saints LB Demario Davis has been key in making this rush defense competent in 2025, but considering the workload, and his 5.4 yards per carry so far this year, Cook will have plenty of opportunity to expose this defense on Sunday.
PrizePicks Projection: James Cook – 16.5 Fantasy Score
Saints RB Alvin Kamara vs. Bills
The Bills have one of the worst rushing defenses in the NFL through three weeks, allowing 6.24 yards per carry — the highest mark in the league. The Bills also rank 28th in rush defense EPA, per rbsdm.
They have surrendered 4 rush TDs, tied for the fifth most. Even more concerning is their vulnerability after initial contact, giving up 2.84 yards after contact per attempt, the fifth worst rate in the NFL.
For the Saints, the lone bright spot in their offense has been veteran RB Alvin Kamara.
Kamara ranks inside the top 15 among all NFL players in missed tackles forced (8), and is averaging 3.7 yards per carry. He’s also gaining 2.38 yards after contact per attempt, which puts him among the more efficient backs when it comes to grinding out tough yards.
PrizePicks Pick: Alvin Kamara – 50.5 Rush Yards
WR vs. CB Matchups to Target: Week 4
Rams WR Davante Adams vs. Colts CB Xavien Howard
Editor's Note: Adams' hamstring strain could limit him this week, though he is expected to play. WR Puka Nacua could get some coverage from Howard instead.
Colts CB Xavien Howard has had a brutal start to the season. Per PFF, he ranks 95th out of 99 qualifying corners in coverage, allowing a 133 passer rating and 9.2 yards per reception.
That’s a dangerous combination when lining up against Davante Adams — who has proven to be quarterback-proof, with five straight 1,000+ yard seasons across four different teams. Over the past three seasons, Adams has produced no matter who's under center, and this season is no different.
He’s averaging 16.4 yards per catch, ranks top 10 in receiving touchdowns, and top 15 in receiving yards. He’s also top 10 in total targets with 28. Stafford has quickly gained trust in Adams, as he has at least 8 targets in ever game this year.
PrizePicks Pick: Davante Adams – 66.5 Receiving Yards
Raiders WR Jakobi Meyers vs. Bears CB Nick McCloud
Bears slot CB Nick McCloud is allowing a 157 passer rating and 14.8 yards per reception when targeted this year. In just 90 coverage snaps, he’s already given up 10 receptions.
That spells trouble with WR Jakobi Meyers lining up in the slot for the Raiders, where he's playing 64.8% of his snaps. . Meyers has been dominant to start the year, ranking top 10 in both receptions and receiving yards.
He’s also 11th in the NFL in targets with 25 and is averaging an impressive 13.4 yards per reception. Meyers leads an offense that has found no success running the ball this year, ranking 31st in EPA allowed per rush (-0.30).
PrizePicks Pick: Jakobi Meyers 65.5 Receiving Yards
Best OL vs. DL Mismatches, Predictions: Week 4
Eagles DL vs. Buccaneers OL
The Tampa Bay Buccaneers offensive line has been one of the worst units in the NFL this season. All things considered, they are also struggling with injuries to start the season. The Bucs have th e20thranked pass blocking grade, per PFF.
To this point, RT Charlie Heck has already allowed 10 pressures in just 140 snaps. Center Graham Barton has surrendered 11 pressures and 2 sacks, and he's also been flagged for 4 penalties all in just 209 total snaps. They will get a huge boost this week with the return of former first-round pick and two-time All-Pro OT Tristan Wirfs, who hasn’t appeared in a game yet this season due to early health issues.
On the other side of the ball, the Eagles defensive line is living up to its reputation as one of the most fearsome in the league. Eagles DT Jalen Carter has racked up 7 pressures and 4 QB hits in just 69 pass rush snaps.
DE Jalyx Hunt has totaled eight pressures and three QB hits in only 56 snaps. Seventh-round gem Moro Ojomo out of Texas has been a diamond in the rough — he currently ranks top 15 among all defensive tackles in pressures, hurries, and sacks.
This has helped the Eagles limit opposing QBs to just 185.7 yards per game passing. The Bucs will be without WR1 Mike Evans in this game, though they do get Chris Godwin back in his first appearance of 2025.
PrizePicks Pick: Bucs QB Baker Mayfield – 220.5 Passing Yards
Chargers DL vs. Giants OL
The Chargers defensive front has become a problem for opposing offenses, despite missing EDGE Khalil Mack since Week 2. DT Teair Tart ranks 10th out of 111 interior defensive linemen in pressure rate this season. On the edge, LB Tuli Tuipulotu is top five in both total pressures and QB hurries, logging 16 pressures, 13 hurries, and 3 QB hits.
Chargers EDGE Bud Dupree has stepped in for the injured Mack. Last year, Dupree proved he still has juice left finishing with 6 sacks and 26 pressures.
The Giants offensive line, however, remains a disaster. C John Michael Schmitz has allowed 7 pressures already and ranks 35th out of 36 qualified centers in the league, via PFF. LG Jon Runyan has given up 9 pressures, 1 QB hit, and 2 sacks in just 200 snaps.
On the right side, Greg Van Roten who was acquired this offseason continues to struggle. Last season, he allowed 35 pressures and 7 sacks, ranking among the league’s worst at the position. They will now need to protect a young inexperienced rookie quarterback in his first career start.
PrizePicks Pick: Jaxson Dart 188.5 Passing Yards
Best TE Matchup: Week 4
Patriots TE Hunter Henry vs. Panthers
The Carolina Panthers linebacker unit has been one of the weakest in coverage this season. LB Trevin Wallace is allowing a passer rating of 114.6 when targeted, ranking 48th out of 64 linebackers in coverage.
LB Christian Rozeboom hasn’t fared much better, ranking 59th out of 64 and allowing a passer rating of 109.2.
This sets up a favorable situation for Patriots TE Hunter Henry, who’s become a reliable safety blanket for second-year QB Drake Maye. Henry ranks top 10 among tight ends in receptions, targets, receiving yards, and yards per reception.
Henry hasalready posted 165 receiving yards, 13 receptions, and two TDs this season, and has earned a stellar 131 passer rating when targeted.
PrizePicks Pick: Hunter Henry – 41.5 Receiving Yards
Make NFL Week 4 Predictions on PrizePicks
Week 4 is here, bringing us another Sunday packed with exciting NFL matchups and divisional games. Use the PrizePicks NFL Cheat Sheet to sharpen your takes and build out your winning Lineups for Sunday.
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Pull up the PrizePicks NFL board, pick at least two players, prediction More or Less on their projections — like yards or receptions — and win real money when you’re right.
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