San Francisco 49ers vs Arizona Cardinals Prediction & Picks - NFL

Prediction published on 9/21/25, 1:13 PM  by Lou Aguila | Modified on 9/22/25 at 9:38 AM in NFL Picks

The San Francisco 49ers will stake their spotless record against the also undefeated Arizona Cardinals on Sunday at Levi’s Stadium.

The Cardinals, who won the last two games against the 49ers, are +110 road underdogs in this match.

Current Form:

Despite losing starting quarterback Brock Purdy to multiple injuries, the 49ers secured their second win of the season after holding off the New Orleans Saints, 26-21, in Week 2. Backup quarterback Mac Jones threw for 279 yards with three TDs in the gallant win. San Francisco also trounced the Seattle Seahawks 17-13 in Week 1.

The Cardinals will also march into week 3 with a 2-0 slate after squashing the Panthers’ second-half run to hang on to a 27-22 win. Arizona also bested the New Orleans Saints 20-13 in Week 1. In that game, the Cardinals' defense made the biggest impact, conceding only one touchdown and forcing Saints quarterback Spencer Rattler to complete only 58 percent of his passes.

Key Statistics:

The 49ers rank fifth in passing yards per game (266.0), 22nd in rushing yards (98.0), and 18th in points per game (21.5). Defensively, San Francisco surrendered the 7th fewest points so far at 17.0 points per game and allowed the 6th fewest total yards per game at 268.5 yards.

The Cardinals rank 27th in the NFL in terms of passing yards (170.5), 13th in total yards (114.0), and 11th in points per game (23.5). They also rank 10th in points allowed per game (17.5).

Quarterback Matchup:

Cardinals QB Kyler Murray (383 yards, 38-54 with 3 TDs and 1 INT) vs. 49ers QB Mac Jones (279 yards, 26-39 with 3 TDs)