Following Sunday’s early morning London game and eight 1:00 p.m. ET matchups, the 4:05 and 4:25 p.m. ET slate has four contests on Sunday, October 4. The Denver Broncos vs. the San Francisco 49ers stands out as the top matchup of the afternoon and perhaps the game of the week.
According to PrizePicks, the 49ers are 2.5-point home favorites on the spread, and that’s backed by a strong 3-0 start and thriving offense. Following Week 1’s 31-10 loss vs. the Chiefs, the Broncos have bounced back with 20-13 and 30-26 wins over the Jaguars and Rams.
In a matchup between potential playoff contenders, let’s jump into our Broncos vs. 49ers prediction and player picks for PrizePicks.
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Broncos vs. 49ers Prediction, Spread, Over/Under – Sunday, October 4
This is a battle between Super Bowl contenders, as the Broncos (14.28x) and 49ers (7.69x) sport the seventh- and third-shortest payouts to win Super Bowl LXI, per PrizePicks. There’s not much room for error, though, as the 49ers are in the league’s best division, contending in the NFC West with the Seahawks and Rams. Meanwhile, the Chiefs and Raiders are each 3-0, posing a serious threat to the Broncos in the AFC West.
The Chiefs have the shortest payout to win the AFC West (1.72x), ahead of Denver’s 2.94x payout, per PrizePicks. Meanwhile, the 49ers’ 2.22x payout to win the NFC West is slightly ahead of the Seahawks (2.94x) and Rams (3.22x).
As usual, the Broncos are led by one of the league’s best defenses, but the unit has shown cracks by giving up 23.3 PPG (17th) and 5.6 yards per play (21st). Meanwhile, the offense has tallied only 20.0 PPG (22nd) and 5.0 yards per play (23rd), and QB Bo Nix has 3 INTs and 1 lost fumble.
The 49ers continue to battle injuries, but that hasn’t stopped San Francisco from tallying 32.7 PPG (second) while allowing only 16.7 PPG (third).
For Sunday, EDGE Nick Bosa (knee, calf) is out alongside second-year EDGE Mykel Williams — who was a limited participant at practice this week as he recovers from 2025’s ACL injury. The front seven could be thin with EDGE Keion White (hamstring), LB Dre Greenlaw (quad), and LB Jaden Dugger (shoulder) all questionable.
Additionally, WR Mike Evans is questionable with a rib injury; this receiving unit is already without WRs Christian Kirk, De’Zhaun Stribling, and Demarcus Robinson.
Broncos vs. 49ers Spread, Over/Under – Sunday, October 4
Following Week 1’s win as an underdog, the 49ers remain in the favored role as 2.5-point favorites on the spread for Sunday, via PrizePicks.
Here are the full payouts for the Broncos vs. 49ers on PrizePicks, including winner payouts, the spread, and the over/under.
Make your Broncos vs. 49ers prediction on the spread on PrizePicks.
PrizePicks data is live at the time of writing and is subject to change.
Broncos vs. 49ers Prediction on Spread – 10/4/26
According to RBSDM, the Broncos carry -0.063 EPA per play on offense (22nd) and allow 0.023 EPA per play on defense (21st). The 49ers’ -0.009 EPA per play allowed (14th) won’t knock your socks off, but their 0.330 EPA per play on offense leads the NFL.
Even more impressive, San Francisco’s 56.0% success rate on offense tops the league. That’s further backed by QB Brock Purdy playing out of his mind with 0.627 adjusted EPA per play (first). For context, Cowboys QB Dak Prescott’s 0.377 adjusted EPA per play is the second-best total; that’s a huge margin!
If this were last season, we’d say the Broncos have the defense to answer the call. After ranking first with a 37.8% success rate allowed in 2025, Denver’s D has given up a 41.9% success rate (10th) through three games.
The secondary is still one of the league’s best with a 42.7% dropback success rate allowed (sixth), and that’s aided by a 55% pass rush win rate (sixth), per ESPN. However, the Broncos are allowing 5.1 yards per carry (30th) and a 40.5% rush success rate (17th).
While Purdy’s excellent play is front and center, don’t forget about 49ers RB Christian McCaffrey, who touts 55.3 rushing yards per game with 4.7 yards per carry. Plus, rookie RB Kaelon Black gives the Niners another option in the backfield with 4.3 YPC.
San Francisco’s offense typically stays on schedule thanks to an efficient run game that features a 49.08% rush-play rate (seventh) and 5.1 YPC (fourth). Further, the offensive line sports a 74% run block win rate (12th) and 58% pass block win rate (fifth) that can help offset this talented Broncos front seven.
On the other side of the ball, the Broncos have struggled to get the run going with 3.6 YPC (29th) and a 35.8% rush success rate (23rd). The 49ers have given up only 3.7 YPC (10th), and if Denver cannot run the rock, it could fail to limit possessions for this elite San Francisco offense.
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Broncos vs. 49ers Picks, Player Stats for PrizePicks: 10/4/26
Here are today’s top Broncos vs. 49ers picks for PrizePicks, including projections for RB J.K. Dobbins and TE George Kittle.
Broncos RB J.K. Dobbins vs. 49ers: 13.5 Rush Attempts
- As mentioned, the Broncos may look to keep the 49ers' offense on the sidelines by running the rock. Despite only 6.5 yards per passing attempt (24th), Denver has a 59.04% pass-play rate (12th). That likely needs to decline today if the Broncos are to control possession.
- J.K. Dobbins is off to an inefficient start with only 3.5 YPC. However, his 2.63 yards after contact per carry still leads the Broncos’ backfield, per Pro Football Focus.
- The offensive line is doing its part with a 75% run block win rate that ranks eighth in the NFL.
- With rookie RB Jonah Coleman on injured reserve, the threat of losing touches has eased for Dobbins. In fact, he comes off a season-high 17 rushing attempts in Week 3’s 30-26 win over the Rams.
- Following Week 1’s 63.6% pass-play rate in a negative game script vs. the Chiefs, Denver featured a 55.1% pass-play rate over the last two weeks. Once again, the run game should be more prominent going forward.
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49ers TE George Kittle vs. Broncos: 63.5 Receiving Yards
- George Kittle may not be human. After tearing his Achilles in January, he was ready for Week 1 and already looks like himself with 5.5 targets, 5.0 receptions, 81.0 receiving yards, and 1.5 receiving TDs per game over his last two games.
- According to PlayerProfiler, Kittle’s 29.6% target rate sits sixth among tight ends, and his 23.2% air yards share (fourth) and 8.9 average depth of target (third) prove the 49ers are willing to push the ball downfield with Kittle.
- Among TEs with at least 10 targets this season, Kittle’s 14.5 yards per reception and 3.11 yards per route run each rank as the third-best mark across the league.
- If Mike Evans is out, more work could come Kittle’s way, and the Broncos have allowed 199 receiving yards to tight ends (ninth-most), per Pro Football Reference.
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Despite several injuries on defense, the 49ers may keep rolling thanks to an elite offense and excellent play from Brock Purdy. The Broncos’ key could be winning the run game on Sunday afternoon. Will Denver find a way to flip the narrative on the ground?
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