49ers vs. Cowboys Prediction, Spread, Week 10 NFL Picks – Sunday, November 15

In Week 10, the San Francisco (7-1) will face the Dallas Cowboys (4-5) at 4:25 p.m. ET on Sunday, November 15. The 49ers enter as 4.5-point road favorites, and they would return a 1.44x payout if they win outright, per PrizePicks.

The Niners are fresh off a 38-17 beatdown of the Las Vegas Raiders and continue to look like one of the NFL’s best teams. On the other hand, the Cowboys were less impressive in Week 9, needing a late touchdown on the road to outlast the rebuilding Indianapolis Colts, 27-23.

Now back on their home turf, can Dallas get a statement win against an NFC contender?

Below, we’ll break down our 49ers vs. Cowboys prediction and picks for NFL Week 10, including the spread, over/under, and top player picks for PrizePicks.

Make your 49ers vs. Cowboys prediction and picks on PrizePicks now!

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49ers vs. Cowboys Prediction, Spread, Over/Under – NFL Week 10

The 49ers enter Sunday’s game as 4.5-point road favorites against the Cowboys, returning a 1.44x payout if they win outright, via PrizePicks — or an estimated $144 on a $100 entry.

Here are the full payouts for the 49ers vs. Cowboys game on PrizePicks. 

PrizePicks data is live at the time of writing and is subject to change. 

Make your 49ers vs. Cowboys prediction on the spread, over/under, and more on PrizePicks!

Despite being down multiple wideouts in Week 9, the 49ers’ offense didn’t miss a beat against the Raiders, tallying 38 points off 414 total yards of offense. The win marked the fourth time the team has exceeded 30 points in eight games.

For the season, the Niners rank third in PPG (29.4) and sixth in YPG (376.8). QB Brock Purdy has been incredibly efficient, ranking first in adjusted EPA/play (0.321), per RBSDM. 

The offense continues to deal with injuries, though, as they’ll once again be without WR Mike Evans, and LT Trent Williams is questionable. The good news is WR Deebo Samuel will return after sitting out last week, and this team still has excellent weapons in RB Christian McCaffrey and TE George Kittle. They also added veteran WR Keenan Allen at the trade deadline. 

San Francisco has also been strong defensively, allowing the sixth-fewest PPG (19.5) and third-fewest YPG (291.9). However, this side of the ball is also banged up, as LB Dre Greenlaw and the team’s top three cornerbacks are all questionable.

The injuries to the 49ers’ secondary could open the door for the Cowboys’ offense to put up numbers. Dallas is sixth in PPG (27.3), and while they’ve had a more balanced attack lately, they rank sixth in passing YPG (256.9) compared to 21st in rushing YPG (103.6). 

Although the Cowboys narrowly defeated the lowly Colts last week, much of that had to do with sloppy play that included 14 penalties for 153 yards and 2 lost fumbles. The team otherwise dominated the stat sheet, outgaining Indianapolis 508 yards to 271 while possessing the ball 59.5% of the time.

QB Dak Prescott threw for 335 yards and 2 TDs behind a massive day from WR CeeDee Lamb, and the run game turned 34 carries into 179 yards and another TD.

Dallas will look for a cleaner effort time around. They’ll also have WR George Pickens back, who missed last week’s game with a hamstring injury.

It’s no secret that the Cowboys’ defense has been the team’s biggest weakness, though, as they’re 25th in PPG (26.2) and 30th in YPG (372.7). Additionally, much like the Niners, Dallas is also dealing with multiple injuries in their secondary.

While the Cowboys’ D performed well last week, this will be a major step up in competition against this potent San Francisco offense.  

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49ers vs. Cowboys Prediction on Spread – 11/15/26

Here are the key stats and trends behind our 49ers vs. Cowboys prediction on the spread for Sunday, November 15.

• The 49ers rank first in both EPA/play (0.163) and success rate (52.5%). They’re also first in offensive DVOA, per FTN. The Cowboys are sixth in EPA/play (0.113), eighth in success rate (47.1%), and sixth in offensive DVOA.
• Even with Evans out the last two games for San Francisco, the offense has averaged 0.118 EPA/play.
• While there are injury concerns for San Francisco’s defense, they’ve been significantly better than Dallas, ranking inside the top 10 in EPA/play (-0.065) and defensive DVOA. The Cowboys’ D is 31st in EPA/play (0.101) and 29th in DVOA.
• Dallas could have a tough time generating pressure on Purdy. Per ESPN, the Cowboys rank 30th in pass rush win rate (43%) and will be up against an offensive line that’s first in pass block win rate (64%). Purdy has the lowest sack rate (3.3%) among qualified QBs this year.
• The Cowboys’ defense really struggles on third down, allowing the league’s highest third-down conversion rate (48.3%), per TeamRankings. Meanwhile, the Niners’ offense boasts the NFL’s second-best third-down conversion rate (51.7%). 
• Penalties have been an issue for Dallas beyond just last week, as they’re 31st in penalty YPG (74.1) in 2026.

Make your 49ers vs. Cowboys picks on PrizePicks for Sunday’s NFL game.

49ers vs. Cowboys Picks, Player Stats for PrizePicks: 11/15/26

Here are the top 49ers vs. Cowboys picks to target on Sunday, November 15. Today’s NFL picks for PrizePicks include Jordan Watkins and Ryan Flournoy.

49ers WR Jordan Watkins vs. Cowboys: 23.5 Receiving Yards

• With Samuel and/or Evans out, Watkins has seen his snap share jump to 74% or better in three straight games, per PlayerProfiler. According to JJ Zachariason, he led the team with 26 routes run (87% share) in Week 9. Even with Samuel back, he could continue to see a big role with Evans still sidelined.
• Over that span, Watkins has tallied 22, 56, and 86 receiving yards.
• Dallas’ defense is 28th in dropback/EPA allowed (0.182) and 27th in dropback success rate (49.0%).
• Per Pro Football Reference, the Cowboys are giving up the ninth-most receiving YPG (159.3) to WRs.
• This matchup has a sky-high 55.5-point total, suggesting we could have a shootout between these two teams. 

Add Jordan Watkins + 49ers to cover the spread to your PrizePicks lineup now.

Cowboys WR Ryan Flournoy vs. 49ers: 36.5 Receiving Yards

• Flournoy is averaging 43.9 receiving YPG this year and has reached 37+ in six straight games.
• He’s seen a solid 14.5% target share and 76.5% route participation rate. Fournoy logged a 97.2% snap share and 94.7% route participation rate with Pickens out last week, so he could see a bump in work if Pickens were to suffer any in-game setback.
• Per PFF, Flournoy has the third-highest missed tackle forced rate (24.2%) among WRs with at least 30 touches this year.
• The Cowboys have leaned more on the run over their last three games, but they may struggle to move the ball on the ground. The Niners’ defense is first in rush EPA/play (-0.215) and allows the fifth-fewest rushing YPG (71.5) to opposing RBs.

Add Ryan Flournoy + Cowboys to win to your PrizePicks lineup now.

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Make 49ers vs. Cowboys Picks on PrizePicks

The San Francisco 49ers have dropped only one game all season, while the Dallas Cowboys have struggled to find consistency. Despite that, can the Cowboys pull off the upset at home?  

Don't wait until kickoff — make your 49ers vs. Cowboys picks on PrizePicks now for Week 10 and earn real money if you're right.

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