Top 3 NFL Games to Bet on in Week 4: Bills, Bears and 49ers Lead the Picks

Week 4 presents three opportunities to back home favorites at spreads that leave room for different game scripts. Buffalo needs a touchdown victory against New England, Chicago must beat the Jets by at least four, and San Francisco can cover against Denver with a three-point win. My selections are Bills -6.5, Bears -3.5 and 49ers -2.5, using the lines supplied for this article. Each pick has a different foundation: Buffalo’s offensive upside, Chicago’s ability to function without its starting quarterback, and San Francisco’s versatility in a matchup that could stay close. These are spread predictions, and the margin matters. Winning the game alone will not cash any of these tickets. Here is why I like each favorite, what could derail the pick, and how I expect the games to unfold.

1. Buffalo Bills -6.5 Over the New England Patriots

Buffalo is my strongest selection because this matchup gives Josh Allen an opportunity to attack a defense missing two important pieces. New England has ruled out cornerback Christian Gonzalez and defensive tackle Christian Barmore with shoulder injuries. Losing help in both coverage and the interior makes defending Buffalo considerably more complicated. reuters.com The concern for New England is how those absences can affect each other. If the Patriots need extra bodies near the line to defend the run, Allen can look for favorable coverage outside. If they prioritize protecting their secondary, Buffalo can stay patient and make the defense tackle through sustained possessions. My expectation is that Buffalo will benefit from keeping the offense balanced. There is no reason to turn every possession into a search for a spectacular play. Efficient early-down gains can create manageable third downs, preserve the full playbook, and force New England to defend more than obvious passing situations. Allen’s ability to extend plays adds another challenge. A defense can handle the initial route combinations and still surrender a conversion when he escapes pressure. Those extra possessions matter when the favorite needs to establish a touchdown margin rather than merely survive a close finish. The spread is the attraction here. At -6.5, a seven-point Buffalo victory covers. That half-point below a touchdown gives us a useful boundary, especially in a divisional game where familiarity can keep the underdog competitive longer than expected. The risk is Buffalo making the game unnecessarily difficult through turnovers or empty red-zone possessions. New England does not have to dominate to cover; it can hang around by shortening the game and capitalizing on mistakes. I want the Bills to take the available gains and finish drives. I expect Buffalo to create separation after halftime as New England’s defensive replacements face repeated pressure. The Patriots could produce stretches of competitive football, but I favor Allen’s ability to sustain the scoring necessary for a clear win. The pick: Bills -6.5 Predicted score: Bills 30, Patriots 20

2. Chicago Bears -3.5 Over the New York Jets

Chicago requires the most careful explanation of these three selections. Caleb Williams has been ruled out with a hamstring injury, and the Bears had not publicly settled their starting-quarterback announcement in the latest reports. Case Keenum and Tyson Bagent were the options. reuters.com That uncertainty matters, but Chicago already demonstrated that its offense can operate effectively without Williams. Keenum completed 70.6 percent of his passes for 247 yards and two touchdowns in a 27–7 victory over Philadelphia. Ben Johnson’s system gave the veteran a productive framework. chicagobears.com My case for the Bears rests on that framework rather than assuming another outstanding individual performance. Chicago should build around accessible throws, a credible running game, and protection that avoids asking its quarterback to rescue too many broken possessions. There is a meaningful distinction between asking a backup to win a shootout and asking him to execute a balanced offense at home. I expect Johnson to favor the latter approach. Chicago can create scoring opportunities through field position and sustained drives without requiring constant downfield aggression. The Jets deserve respect. Their official preview highlighted Geno Smith’s strong early-season performance, and New York enters this matchup at 1–2 against a 2–1 Chicago team. The Bears cannot assume quarterback uncertainty automatically applies equally to both sides. newyorkjets.com For Chicago to cover, its defense needs to make New York work through full possessions. Quick scoring drives would put more pressure on the Bears’ quarterback and make the game less comfortable. Tackling and third-down execution are central to this prediction. At -3.5, a field-goal victory is insufficient. That makes this selection more demanding than taking Chicago simply to win. I expect a competitive game, but I see the Bears producing enough offense to secure a late touchdown margin. The pick: Bears -3.5 Predicted score: Bears 27, Jets 20

3. San Francisco 49ers -2.5 Over the Denver Broncos

San Francisco offers my preferred spread structure of the three games. At -2.5, a three-point victory is enough. That matters against Denver because I expect a competitive matchup rather than an easy afternoon. The injury picture prevents an overly confident assessment. San Francisco ruled out Nick Bosa, Mykel Williams, and James Thompson Jr., while Mike Evans was questionable. Those absences make containing Denver’s offense more difficult and put greater responsibility on the available defenders. 49ers.com My prediction therefore depends on San Francisco’s offense controlling stretches of the game. Brock Purdy can benefit when the 49ers stay ahead of the chains and force Denver to account for the running game alongside underneath receiving options. Christian McCaffrey gives that approach flexibility. I expect San Francisco to use his versatility to create manageable situations and make Denver defend the width of the field. The objective should be steady production that reduces the pressure on a depleted defensive front. Denver’s path is clear: disrupt that rhythm, create long-yardage situations, and keep Bo Nix from having to chase the score. If the Broncos succeed, this could become a possession-by-possession finish. I still favor San Francisco at home. My expectation is that its offensive options produce the decisive scoring drive, even if Denver remains within reach throughout. The pick: 49ers -2.5 Predicted score: 49ers 27, Broncos 23

Final Week 4 Picks

Buffalo is my top selection, Chicago carries the greatest quarterback uncertainty, and San Francisco benefits from a spread below three. At the supplied numbers, my card is Bills -6.5, Bears -3.5, and 49ers -2.5.