San Francisco had extra time to prepare after edging the Los Angeles Rams 26-23 in overtime on Week 5 Thursday Night Football. That game showcased both the 49ers’ resilience and their mounting injury challenges. With Brock Purdy sidelined, Mac Jones played through multiple ailments. He delivered a gritty 342-yard, two-touchdown performance despite taking several hard hits. The win, though costly, gave head coach Kyle Shanahan’s team momentum heading into a crucial road test.

On the other side, Baker Mayfield and the Buccaneers enter brimming with confidence after a 38-35 shootout win over Seattle. Tampa Bay’s balanced attack makes them one of the most complete teams in the conference.

A measuring stick for both teams

For the 49ers, this game represents a test of depth and durability. Injuries to key offensive players have forced Shanahan to rely heavily on Christian McCaffrey and the short passing game. However, but Tampa Bay’s front seven is one of the most disciplined in football. The 49ers will need Jones to find success on early downs to avoid long-yardage situations against a pass rush led by Vita Vea and Lavonte David.

Tampa Bay, meanwhile, sees this as a chance to validate its standing among NFC heavyweights. The Buccaneers’ offense has been explosive even without Mike Evans. That’s thanks to Emeka Egbuka’s emergence as a legitimate downfield threat. With Mayfield’s efficiency improving week by week, head coach Todd Bowles has found the right blend of controlled aggression.

Both defenses are elite at limiting the run and creating pressure. As such, whichever quarterback stays upright and mistake-free will likely decide this one.

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Here we will look at and discuss some bold predictions for the game between the 49ers and the Buccaneers in Week 6 of the 2025 NFL season.

Mac Jones starts but struggles

Mac Jones is expected to start for San Francisco despite knee and oblique injuries. That said, his health and protection will be key concerns. Jones has shown toughness and command under Shanahan’s scheme. Still, Tampa Bay’s defense presents a more formidable challenge.

Jones’ tendency to hold the ball under pressure could spell trouble against the Buccaneers’ front seven. Expect Shanahan to rely heavily on quick throws, screens, and motion-based plays to keep the pass rush honest. Even so, Jones may struggle to sustain drives or generate big plays downfield. A stat line around 220 passing yards, one touchdown, and one interception feels realistic against this aggressive Tampa Bay defense.

Christian McCaffrey limited to under 100 total yards

When healthy, Christian McCaffrey is San Francisco’s engine. He is a threat to score from anywhere on the field. However, the Buccaneers’ defensive scheme is tailor-made to limit backs like him. Tampa Bay ranks among the top five in run defense. As of this writing, they allow fewer than 85 rushing yards per game.

McCaffrey posted 139 total yards and a touchdown against the Rams last week. Remember, though, that it came with a heavy volume of 30 touches in total. Against Tampa Bay, expect the workload to remain high but the efficiency to dip. With linebackers David and Haason Reddick patrolling the middle, McCaffrey may find little room to maneuver. Even as a receiver, he’ll likely see bracket coverage on key downs. Look for him to finish with under 100 total yards.

Niners can’t contain Emeka Egbuka

Few players have been as impactful for Tampa Bay in recent weeks as Egbuka. He has stepped seamlessly into the WR1 role, posting back-to-back 100-yard games. Those were capped by a 163-yard, one-touchdown effort against Seattle. His chemistry with Mayfield is undeniable.

Note that San Francisco’s secondary, while physical, has struggled against shifty route-runners. Egbuka’s precision and separation ability could prove problematic for corners tasked with man coverage responsibilities. Expect him to log another seven-plus catches and 100+ yards. He will continue his torrid pace and punish any defensive lapses the 49ers make.

49ers crushed by Baker Mayfield’s clutch performance

Say what you will about Baker Mayfield. He has been one of the most reliable closers in the NFL this season. He has guided the Buccaneers to four wins, with three of them featuring fourth-quarter scoring drives. Against the 49ers’ vaunted defense, his poise under pressure will again be tested. So far, though, he’s passed every challenge.

San Francisco’s defensive front remains vulnerable to mobile quarterbacks who can extend plays. Mayfield’s off-script creativity and quick decision-making will be crucial. Expect him to throw for 250+ yards and two touchdowns, adding a few key scrambles to move the chains. More importantly, he’ll make the right plays late to secure another Tampa Bay win.

Bottom line

This game has all the makings of a playoff-caliber battle. That said, the 49ers’ injuries and offensive limitations may prove too much to overcome against a Buccaneers squad firing on all cylinders. Expect Tampa Bay to control the tempo, win the turnover battle, and capitalize late behind Mayfield’s composure. We have the Buccaneers winning, 27-23. Tampa Bay sends a message to the rest of the NFC: the road to the conference crown might just run through Raymond James Stadium.