Rams vs. 49ers prediction and fantasy outlook for Week 5 TNF feat. Christian McCaffrey, Puka Nacua, and more

Week 5 of the 2025 NFL season kicks off with Thursday Night Football between the Los Angeles Rams and San Francisco 49ers. Both teams enter this contest with a 3-1 record, so the outcome will have a major impact on the NFC West divisional standings. Here's how things could play out in this game, as well as some of the top picks for fantasy football.

Week 5 Rams vs 49ers prediction

Rams vs 49ers prediction

The 49ers will enter this matchup against the Rams missing many of their star players as they are currently plagued by injuries. Brock Purdy, Ricky Pearsall, and Jauan Jennings have all been ruled out, while Nick Bosa, George Kittle and Brandon Aiyuk remain on the injured reserve list.

The Rams are in the opposite situation as they will be playing with a relatively healthy lineup that includes most of their ususal starters. This should give them a significant on TNF, esepcially since it will be played in their home stadium as well.

Prediction: Rams 27 - 49ers 16

Rams vs 49ers Week 5 fantasy outlook

TNF fantasy outlook

Christian McCaffrey, RB, San Francisco 49ers

Christian McCaffrey has surprisingly failed to score a rushing touchdowns this year, but he has still finished as the RB8 or better in all four of his games. He is already averaging 25 touches per game and could be asked to handle an even larger workload this week with so many of the 49ers' weapons injured. He is one of the bst running backs to target for Week 5 fantasy football.

Kyren Williams, RB, Los Angeles Rams

Kyren Williams remains the featured running back for the Rams, despite Blake Corum receiving an elevated role in their offense this season. Williams still currently ranks as the overall RB17 and has recorded at least 16 touches in all four games. The Rams are heavily favored in this game, so he could see additional carries if they get out a big lead as expected.

Puka Nacua, WR, Los Angeles Rams

Puka Nacua is having an incredible 2025 fantasy football season. He has finished as the weekly WR8 or better in all four of his games and currently ranks as the QR1 overall, despite only having scored two touchdowns. His massive 42 receptions on 50 targets gives him one of the safest worklaods in the league and also puts him among the top picks for Week 5 lineups.