NFL Week 4 Opening Lines, Odds & Best Bets: 49ers look superior in potential Super Bowl preview vs Broncos

On the heels of a wild Week 3 in which a whole host of games went down to the wire, Week 4 of the 2026 NFL regular season is on the immediate horizon. It kicks off with Thursday Night Football between the AFC North rival Steelers and Browns, while the other primetime matchups are Lions vs Panthers and Falcons vs Saints. Patriots vs Bills, Rams vs Bengals, Chiefs vs Raiders and Broncos vs 49ers also headline a jam-packed slate. 

Make sure you check out our NFL predictions as we add our picks on the side and total for every game throughout the week – and throughout the entire season. Also don't miss the NFL best bets page for our top picks. For now, let's break down the NFL Week 4 opening lines and give our best early bet to make.  

NFL Week 4 opening lines and odds  

Odds available at DraftKings Sportsbook at time of publishing  

• Pittsburgh Steelers -2.5 (-110) vs Cleveland Browns +2.5 (-110) - Thursday Night Football 
• Indianapolis Colts -3.5 (+100) vs Washington Commanders +3.5 (-120) - London 
• New England Patriots +6.5 (-105) vs Buffalo Bills -6.5 (-115)  
• New York Jets +3 (-110) vs Chicago Bears -3 (-110) 
• Jacksonville Jaguars +2.5 (-110) vs Cincinnati Bengals -2.5 (-110) 
• Arizona Cardinals +1.5 (-120) vs New York Giants -1.5 (+100) 
• Los Angeles Rams -1.5 (-115) vs Philadelphia Eagles +1.5 (-105) 
• Green Bay Packers -3.5 (-110) vs Tampa Bay Buccaneers +3.5 (-110)    
• Tennessee Titans +11.5 (-110) vs Baltimore Ravens -11.5 (-110) 
• Dallas Cowboys +2.5 (-110) vs Houston Texans -2.5 (-110) 
• Miami Dolphins +9.5 (+100) vs Minnesota Vikings -9.5 (-120) 
• Kansas City Chiefs -4.5 (-110) vs Las Vegas Raiders +4.5 (-110) 
• Denver Broncos +2.5 (-105) vs San Francisco 49ers -2.5 (-115) 
• Los Angeles Chargers +6.5 (-105) vs Seattle Seahawks -6.5 (-115)  
• Detroit Lions -3.5 (-105) vs Carolina Panthers +3.5 (-115) - Sunday Night Football  
• Atlanta Falcons +2.5 (-104) vs New Orleans Saints -2.5 (-118) - Monday Night Football 

Best bet for NFL Week 4: San Francisco 49ers -2.5 over Denver Broncos (-115)  

It’s hard to be convinced by the Broncos (2-1) even though they managed to “beat” the Rams on Sunday Night Football. And, yes, “beat” belongs in quotes. Denver was playing at home and did not have to face either DE Myles Garrett or WR Puka Nacua and still needed significant help from the officials to survive 30-26 in a thriller that came down to the final play. It would have been over several minutes earlier if Los Angeles CB Josh Wallace had been correctly awarded a game-clinching interception instead of getting hit with an incorrect pass interference call. 

Whatever the case, San Francisco (3-0) appears to be the far superior side at this point. The 49ers are undefeated and have defeated opponents by a combined 48 points. Brock Purdy is playing at an MVP level in the early stages of the season, while the Niners finally have something close to a clean bill of health on the defensive side of the ball. Denver’s only foray away from home so far this season resulted in a 31-10 loss at Kansas City, so I can’t see the visitors staying with a field goal on the road against one of the best teams in the NFL. 

We'll have NFL picks for every game in Week 4!