Running Back Matchups to Target in Week 4 (2025) - James Cook, Kyren Williams, Bucky Irving, More

Thunder Dan's favorite RB matchups to exploit for Week 4 of 2025 - DFS running backs to target on DraftKings and FanDuel. These RB matchups are GPP and cash game opportunities.

If you're looking for some confirmation bias as to why you should deploy matchup-proof running backs like Christian McCaffrey or Bijan Robinson this week, then look elsewhere, friends!

I'm breaking down DVOA data, offensive line matchups and ratings, and various other metrics in an attempt to validate some of those matchups that pop at first glance and perhaps unearth some sneaky good spots at the same time.

My goal in this weekly article will be to highlight the absolute best matchups for running backs on Sunday's main slate, with a primary focus on DFS. However, these are also running backs that you should smash into your season-long lineups and great candidates for prop bets, too. Let's get to it. Here are my top four matchups for Week 4.

• 2025 fantasy football rankings
• Running back (RB) rankings
• Wide receiver (WR) rankings
• Quarterback (QB) rankings
• Tight end (TE) rankings
• Defense (D/ST) rankings
• Kicker (K) rankings
• FLEX rankings
• Dynasty rankings

Week 4 Running Back Matchups

In my constant search for usable data, I crunched the first two weeks of numbers to come up with some metrics. The first column is the overall offensive rushing attack vs. their opponent, calculated using each team's offensive and defensive DVOA. The second column is the offensive vs. defensive line matchup, calculated by using the "adjusted line yards" created and allowed by each team. The third column is simply Pro Football Focus's run-blocking grade for each team's offensive line.

Remember, we are focusing only on the Sunday main slate, so while Jordan Mason (Sunday morning) and J.K. Dobbins (Monday night) both look promising, they don't qualify as picks for this piece.

James Cook ($7,100 DK, $8,500 FD)

Buffalo Bills vs. New Orleans Saints

You probably can't go wrong playing any of the Bills on Sunday as they've been one of the top offenses in the NFL thus far and are 16.5-point favorites at home against a Saints team that is still searching for its first win after getting waxed by 31 points last week.

As they did last year, the Bills are running over opponents in 2025. They rank seventh in rushing DVOA with Cook and arguably the best running QB in football, Josh Allen, leading the way.

The Bills being able to go under-center and run the football has made their offense nearly unstoppable (2nd in rush EPA).

It's enough to worry about Josh Allen. Now, they can just run you over with James Cook, too. pic.twitter.com/SfMwPEQczB

— Evan Lazar (@ezlazar) September 25, 2025

Cook has gone over 100 scrimmage yards in all three of Buffalo's games this season, doing most of his damage on the ground the last two weeks against the Jets and Dolphins. Buffalo's matchup ranks third-best on the slate in my model (pictured above), and they've received the best run-blocking grade (by a pretty wide margin) from PFF through three games.

As a huge home favorite, it's hard not to like Cook this week. The Bills love to run the football, especially if they get a big lead early. Despite scoring four rushing touchdowns already this season, Cook is still projected to be more lightly rostered than a handful of other backs in DFS contests. This is not a spot to get cute. I would make sure you have some exposure to Cook in tournaments, as he has a clear path towards an RB1 finish.

Kyren Williams ($6,300 DK, $7,800 FD)

Los Angeles Rams vs. Indianapolis Colts

Not many folks probably expected Kyren Williams to have his big breakout game of the season against the vaunted Eagles defense, but sure enough, that's what happened in Week 3. The Rams' lead back racked up 112 yards from scrimmage on 22 touches and had a receiving touchdown.

Kyren Williams has a TD!

LARvsPHI on FOX/FOX Onehttps://t.co/HkKw7uXVnt pic.twitter.com/LGRf6BFsRq

— NFL (@NFL) September 21, 2025

He's my favorite sneaky play of the week, as I don't think he will be very popular, and he feels about $1,000 too cheap for his workload and touchdown upside. There was some noise about Blake Corum potentially eating into Williams' touches after Williams ran for just 66 yards in each of the Rams' first two games. However, he put those rumors to rest with last week's performance, and we saw that his coach continued to trust him as his bell-cow in an important game against a quality opponent.

So far, the Colts' defense has been more exploitable on the ground than through the air. So while everyone is jamming Puka Nacua into their cash lineup, you can get some leverage on the field by deploying Williams in tournaments as part of a game stack of the highest total (49.5 points) on the board.

Bucky Irving ($6,900 DK, $7,300 FD)

Tampa Bay Buccaneers vs. Philadelphia Eagles

I just got done discussing how the Eagles have been surprisingly soft against the run this season, with Williams really exposing them last week. Is it time for Bucky Irving to do more damage against the Eagles' run defense this week?

We have yet to see Bucky really bust loose this year, but he finished last season on an absolute tear, racking up some huge totals down the stretch both as a runner and a receiver. He has yet to run for more than 71 yards this year, but he has racked up 121 and 99 yards from scrimmage in his last two games.

He handled 29 touches last week, dispelling any notions that Rachaad White is anything other than a complementary option behind White. This is not a timeshare, folks!

With the Bucs down at least one receiver (Mike Evans) and with another one potentially out or limited this week (Chris Godwin), don't be surprised if they lean on Bucky hard this week. He should be getting at least one, and maybe two, of his starting linemen back, which is only going to help him find some more openings on the interior against the Philly front seven.

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Omarion Hampton ($5,900 DK, $7,000 FD)

Los Angeles Chargers at New York Giants

It's officially Hampton week, and the hype surrounding the talented rookie has been building all week as he gets a matchup with one of the worst run defenses in the NFL. Last week, Hampton broke out with a huge game against Denver, totaling 129 yards from scrimmage on a season-high 25 touches and finding the end zone.

Omarion Hampton's first NFL TD!

DENvsLAC on CBS/Paramount+https://t.co/HkKw7uXVnt pic.twitter.com/o65ViiNCR5

— NFL (@NFL) September 21, 2025

With Najee Harris going down for the season last week, Hampton is now the main back in the Chargers' backfield. If we expect him for another 20+ touches this week, then it's hard not to love him at his current price. The Chargers have been a more pass-heavy offense so far this season, but as touchdown favorites on the road, this could easily swing into a game script where they run the football and feed Hampton.

We expected the Chargers to be a run-heavy offense this season, and in situations where they can get out in front early, I think we can safely predict a lot of rushing volume for this offense. This week feels like a smash spot for Hampton and the run game.

Tony Pollard ($5,600 DK, $6,200 FD)

Tennessee Titans at Houston Texans

There hasn't been much to like about the Titans' offense so far in 2025; however, this week presents an opportunity for them to possibly make some noise and pick up their first win as they face another winless team - the Houston Texans.

Pollard has been handling the bulk of the touches for the Titans in the backfield as Tyjae Spears has spent the first three games on injured reserve. He's out for at least one more game, leaving Pollard with another opportunity to pile up 20+ touches in what grades out as a pretty good matchup.

Houston's pass defense has been solid, but they have been relatively soft on the ground. Tennessee's offensive line projects to have the fourth-best matchup on the Sunday slate. With a rookie quarterback facing a pretty decent Houston pass rush, Tennessee would be wise to feed Pollard and establish the run game in this one. While Pollard hasn't popped off with any huge yardage totals yet, he's been running hard and grinding out some tough yards.

His price is appealing here when you consider that he's heading for another week with a large volume of touches. He can make value in several different ways, whether it be through finding the end zone or piling up catches.

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