The two franchises have met 65 times since 1950. San Francisco holds the edge with 37 wins.
Week 16 marks the San Francisco 49ers final road trip of the season as they head to Detroit for a matchup against the Lions.
At 4-10, the 49ers will look to end their season on a high note against a team they've beaten in nine straight meetings and 14 of the last 15.
The Lions enter the game with a 5-9 record, but they've won four of their past six contests. Detroit is led by a potent passing attack, headlined by quarterback Matthew Stafford and receivers Calvin Johnson and Golden Tate.
Here are five things to watch in Week 16.
1. New faces on offense
San Francisco will have multiple new starters on Sunday due to injuries to Marcus Martin (concussion) and Shaun Draughn (knee), who were both ruled out on Friday.
After starting the team's first 13 games at center, Martin played right guard against the Cincinnati Bengals in Week 15. Erik Pears moved over to right guard after Martin went down while Trent Brown stepped in at right tackle. That means Brown could be in line for his first career start against the Lions.
At running back, there are nearly 17 touches that will go elsewhere with Draughn missing the game. That's what Draughn had been averaging in his six games since joining the 49ers.
Newly signed DuJuan Harris and Kendall Gaskins should shoulder the workload. Gaskins carried the ball twice and caught six passes after Draughn left the game against the Bengals.
Another member of the 49ers backfield who could play a pivotal role on Sunday is…
2. The "Hayne Plane"
San Francisco recalled Jarryd Hayne on Saturday from the team's practice squad while Alex Boone (knee) was placed on the Injured Reserve List. Hayne had been on the practice squad since Week 8. Before that, the running back was active for the first six games of the season, running the ball eight times for 25 yards and catching one pass for seven yards.
Hayne's role in the offense is unknown, but the rookie could also factor into the return game. Hayne has eight punt returns on the season for 76 return yards, including a long of 37 yards.
First thing's first, however, as everyone will be watching to see if Hayne is a part of the 46-man gameday roster.
3. Another milestone for Boldin
A few weeks after reaching 13,000 receiving yards, Boldin is one catch shy of 1,000. The wideout has 59 receptions this season and 999 for his 13-year career. Boldin will just be the 13th pass-catcher in NFL history to reach the milestone and will tie Hines Ward in the process.
Boldin currently ranks fourth on the all-time list among active receivers, behind only Indianapolis Colts receiver Andre Johnson (1,046), Dallas Cowboys tight end Jason Witten (1,013) and Arizona Cardinals receiver Larry Fitzgerald (1,008).
4. Staley vs. Ansah
Joe Staley said earlier in the week that he was looking forward to his matchup against Ezekiel Ansah. Detroit's top pass-rusher leads the Lions with 13.5 sacks, four forced fumbles and two fumble recoveries on the year.
The pair of Pro Bowlers will feature the marquee 1-on-1 battle in the game.
5. Start fast
Another week, another opportunity to put an end to San Francisco's early-game struggles, where the 49ers are yet to score a first-quarter touchdown this season. That will be the focus once again for Blaine Gabbert and Co. in this one.