Lions vs. Cardinals odds, picks, NFL Week 5 prediction, spread, line: start time, betting preview, best bets

One of NFL Week 5's most intriguing games takes place in the desert as the Detroit Lions visit the Arizona Cardinals at State Farm Stadium in Glendale, Ariz. The Cardinals come in at 1-3 and have lost three in a row since beating the Chargers in Week 1, while Detroit is 2-2 after losing to Carolina in a Sunday Night Football shootout. Neither defense has been impressive, so this one has the makings of another high-scoring affair. Kickoff is set for 4:25 p.m. ET. The Lions are 5.5-point favorites, and the Over/Under is set at 54.5 DraftKings Sportsbook. Spend $5+ on Lions-Cardinals in Week 5 with the latest DraftKings promo code and get $150 in bonus bets:

We're breaking down the latest Lions vs. Cardinals odds from DraftKings Sportsbook and have our best bets for the game, using data from the SportsLine Projection Model. The model simulates every NFL game 10,000 times and is up well over $7,000 for $100 players on betting sites on top-rated NFL picks since its inception. The model entered Week 5 of the 2026 NFL season on a 55-44 run on top-rated picks dating back to 2024. Anybody following its picks at NFL betting sites could have seen strong returns.  

Lions vs. Cardinals betting odds (via DraftKings)

Lions vs. Cardinals betting preview

These defenses need a lot of work done. The Lions are giving up the most yards and passing yards in the NFL this season and are 31st in scoring defense at 31.8. Only New Orleans is worse.

That's music to the ears of Jacoby Brissett and the Cardinals. Arizona has its faults, to be sure, but it has a lot of playmakers on offense. Tight end Trey McBride has 46 targets and has converted those looks to 33 catches, 242 yards and two touchdowns. Michael Wilson has 258 yards and a score this year, Marvin Harrison Jr. found the end zone last week and the team has an intriguing running back room with Jeremiyah Love and Tyler Allgeier. 

The Cardinals' defense is also suspect, and the Lions have one of the best offenses in the NFL this year. Arizona is 29th in scoring defense and the Lions are fifth in points per game at 29.8. Jared Goff has nine touchdowns to no interceptions, and Jahmyr Gibbs has seven total touchdowns on the year. 

With poor defenses and good to great offensive personnel on each sideline, points are to be expected, as evidenced by an Over/Under betting line of 54.5 at DraftKings. Wager on NFL Week 5 games, including Lions-Cardinals, with the latest BetMGM bonus code CBSSPORTS to get up to $1,500 in bonus bets:

Lions vs. Cardinals picks, prediction

Lions -5.5

The SportsLine model is leaning toward the Lions here. Detroit is a 5.5-point spread betting favorite despite being on the road, and the Lions have the makings of the NFL's best and most balanced offense. The issue is the defense, which has yet to allow fewer than 24 points in a single game this year. The Cardinals' offense has intriguing talent, but it's been a bit inconsisent, scoring 26, 7, 30 and 24 points this year. Can Arizona keep up? The model doesn't think so, with Detroit covering in 51% of simulations.