NFL Odds for Week 5: Opening Betting Lines, Spreads & Totals – Chargers poised to bounce back

Week 5 of the 2025 NFL regular season is on the immediate horizon, and it is shaping up to a fun one. The lineup begins with a Thursday Night Football showdown in the NFC West between the 3-1 49ers and the 3-1 Rams. Primetime games later in the week include both Buffalo and Kansas City, while a huge Sunday afternoon battle pits Tampa Bay against Seattle. Byes begin this week – but even with 4 teams off, we still have 14 games to watch across Thursday, Sunday and Monday.  

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 make sure to check out our NFL best bets page for our top picks. For now, let’s break down the NFL Week 5 opening lines and give our best early bet to make.  

NFL Week 5 opening lines and odds  

Odds available at DraftKings Sportsbook at time of publishing  

• San Francisco 49ers +3 (+100) vs Los Angeles Rams -3 (-120) – Thursday Night Football  

• Minnesota Vikings -4.5 (-110) vs Cleveland Browns +4.5 (-110) – NFL London Games 

• Las Vegas Raiders +6.5 (-110) vs Indianapolis Colts -6.5 (-110)  

• New York Giants -2.5 (-110) vs New Orleans Saints +2.5 (-110) 

• Dallas Cowboys N/A vs New York Jets N/A

• Denver Broncos +5.5 (-110) vs Philadelphia Eagles -5.5 (-110)    

• Miami Dolphins -1.5 (-110) vs Carolina Panthers +1.5 (-110) 

• Houston Texans N/A vs Baltimore Ravens N/A

• Tennessee Titans +8.5 (-105) vs Arizona Cardinals -8.5 (-115) 

• Tampa Bay Buccaneers +2.5 (+100) vs Seattle Seahawks -2.5 (-120) 

• Detroit Lions -8.5 (-110) vs Cincinnati Bengals +8.5 (-110) 

• Washington Commanders +3 (-115) vs Los Angeles Chargers -3 (-105) 

• New England Patriots +8.5 (-110) vs Buffalo Bills -8.5 (-110) – Sunday Night Football 

• Kansas City Chiefs -3 (-115) vs Jacksonville Jaguars +3 (-105) – Monday Night Football  

Best bet for NFL Week 5: Los Angeles Chargers -3 over Washington Commanders (-105)  

After missing the last 2 games, Jayden Daniels’ status for Week 5 is obviously up in the air at this point. Terry McLaurin was also sidelined from Sunday’s 34-27 loss at Atlanta. Even if those guys are on the field, I still don’t have a ton of faith in the Commanders. Both Marcus Mariota and Deebo Samuel have performed well while picking up the slack from Daniels and McLaurin, but it still didn’t matter against the Falcons. Washington’s defense got gashed by a Michael Penix-led offense that was shut out 7 days earlier by Minnesota. 

The Chargers endured a classic letdown game against a weak opponent (the Giants) after they let their heads get too big following a 3-0 start. Now they return home, and the story should be much different – as you have to think that head coach Jim Harbaugh’s team will play with a lot more fire on the heels of its first loss. Los Angeles is a superior squad and it has home-field advantage, so giving just a field goal represents outstanding value. 

We’ll have NFL picks for every game in Week 5!