The last time Tampa Bay went 5-1 was in 2021 - they went on to win the NFC South division with a 12-4 record.
As for the 49ers, they'll be looking to start 5-1 for the second time (2023) in three years. They ended up 12-5 and atop of the NFC West division, ultimately losing in the Super Bowl to the Kansas City Chiefs.
Both teams are coming off big wins against NFC West opponents - the Niners over the Los Angeles Rams and the Bucs over the Seattle Seahawks.
The two have been playing against each other since 1977, with San Fran holding a dominating 21-7 record over the Bucs.
Tampa Bay has lost four straight to the Niners, with their most recent from last in which they lost 23-20. But can the Bucs stop the losing streak in our spotlight game of the week?
As for the injury reports...
The Bucs will be without offensive stars Mike Evans (WR), Chris Godwin (WR), and Bucky Irving (RB) during this week's matchup against the 49ers. Cornerbacks Zyon McCollum and Benjamin Morrison will also be out.
As for the Niners, they'll be with the following: Brock Purdy (QB), Ricky Pearsall (WR), Jordan Watkins (WR), Yetur Gross-Matos (DE), and Kevin Givens (DT), while star defensive end Nick Bosa remains on injured reserve.
Backup quarterback Mac Jones, who has started in three games this year, is listed as questionable for the Week 6 matchup after being a limited participant in practice all week with knee and oblique injuries.
The Buccaneers are 3.5-point favourites over the Niners with the over-under set at 47.5.
So, who will move on to become 5-1? Let's break it down.
Tampa Bay Buccaneers
All four of the Bucs' wins this season have come off game-winning drives led by quarterback Baker Mayfield. They boast the No. 11 offence (No. 7 in scoring) and the No. 11 defence (No. 23 in scoring).
They've forced four turnovers, committed two, and have only gotten to the quarterback 10 times (23rd) this season.
Tampa is coming off a clutch 38-35 win over the Seahawks in front of the Seattle faithful last week, making it five straight games to start the year where all of their games have been decided by six points or less.
They put up a season-high 426 yards, along with tying their 25 first downs they put up in Week 1, without both Evans and Irving present due to injuries.
Now, Mayfield will be without both of them for another week, with Godwin joining them, leaving rookie wide receiver standout Emeka Egbuka looking to be Mayfield's go-to guy yet again.
The Bucs' rookie, who's currently atop our Rookie of the Year tracker, has put up at least 100 yards in back-to-back weeks with at least one touchdown.
But here's what the Bucs need to do in order to win against the 49ers...
Firstly, keep the 49ers off the field as much as possible. In three of their four wins this season, they've dominated in time of possession.
They've established that they can thrive with Jones at QB despite a lot of key players not on the field. So long as the offensive line, Jones, and Christian McCaffrey are playing, they have a chance to win.
This is tough for a Bucs team that ranks 22nd in rushing offence and relies heavily on their passing game, much like San Fran, but it's needed this week or else it'll be yet another shootout.
The saving grace, if this were to happen, is that the 49ers and the winless New York Jets are the only two teams in the NFL so far this season who have yet to force an interception.
Secondly, do not be shy about blitzing. The best thing you can do against a team that's weak at wide receiver is to put pressure on their quarterback as much as humanly possible.
The matchups aren't in their favour as mentioned before, but it will give their big man, Vita Vea, either more one-on-one opportunities or he'll take on two linemen at once, giving way to any linebackers or defensive backs that they can send.
Despite defensive ranks, Tampa Bay is sixth in both blitz rate (33.9%) and pressure rate (42.9%), and fifth in pass rush win rate (47%) - all three are higher than any other defence the 49ers have faced.
Lastly, they need to just do their thing. I would say to get out to an early lead, but they seem to thrive the best when the pressure is on the most. Just continue to do what they've been doing this season, playing at a high motor as soon as the ball is snapped.
San Francisco 49ers
Probably the team that has defied all odds this season, despite their haunting list of key injuries. They miraculously have the No. 5 overall offence (No. 1 in passing), but their defence sits in the middle of the pack at 16th.
They're 3-0 with Jones under center - all without star tight end George Kittle and No. 1 wide receiver Brandon Aiyuk.
The Niners' offensive line allowed just one sack against the league's No. 2 pass rush last week in their win over the Rams, allowing Jones to put up the second-most passing yards (342) of his NFL career against a No. 2 pass defence.
Wide receiver Kendrick Bourne, for the first time in his nine-year career, put up over 100 receiving yards, setting a career-high with 142, proving head coach Kyle Shanahan can gameplan with any players against any team.
It'll be a battle of battered offences as a lot of star power will be on the sidelines.
So, here's what the 49ers need to do in order to win against the Bucs...
Firstly, control the tempo. Nothing pisses off a high-motor team like the Bucs, or any in any sport, when you control the tempo of the game.
Keep that time of possession on your side for as long as possible and do not commit the little penalties. The Niners have only five false starts and one delay of game penalty this season. However, they're tied for the third most offensive holdings (6).
If the team avoids the little things that will force them on long-yardage situation, their offence will be golden.
Secondly, target Egbuka on defence with Evans and Godwin out. Mayfield has full trust in the rookie to make the big plays at this point. He's fourth in the league in receiving yards (445), yards per game (89.0), and yards per reception (17.8).
Shut down Egbuka with safety help over the top and they'll take away a vital piece of the Bucs offence.
Lastly, get that defence to force that first interception of the season. It's not a coincidence that the Philadelphia Eagles forced Mayfield's one and only interception this season and they ended up winning by six points.
Have the corners play overaggressive and jump the routes. If their receivers get by, then take that chance if safety help is over the top. Punch the ball and attack in the air as much as possible.
Do that and your top offence will handle the rest. As I said earlier, the longer the 49ers can have the ball, the better.
49ers vs. Buccaneers roundup
San Fran is 3-0 on the road this season. After defeating a very good Rams team in their own stadium, they'll be put to another tough test against a feisty Bucs team.
A loss for either team here won't defy their seasons, but a win could surely prove to be vital for a 49ers team in a tough NFC West.
The Bucs have no real threat to them in the NFC South. At this point, they want home-field advantage in the playoffs - and that's where a win here could be handy when Week 17 rolls around.
I'm either expecting a shootout between these two teams or the total opposite, with basically half of the starting receivers out for the matchup between both teams.