Indianapolis Colts vs San Francisco 49ers Prediction & Picks - NFL

USA - NFL

Indianapolis Colts
12/22/25 20:15
San Francisco 49ers

Prediction:

 

49ers -5.5.

-115
$350 offered for betting!

New customers only | Commercial content | 21+ age limit | T&Cs apply

 by Carlos Zabala | in NFL Picks

The 49ers made the most of their bye week, defeating the Titans 37-24 the following week, aided by three touchdown passes from Purdy. Purdy completed 23 of his 30 passes, a clear indication that he is fully recovered from his toe injury. With the win against Tennessee, the 49ers need only one more victory to secure a playoff spot, which they will pursue on Monday, December 22, when they are 5.5-point favorites to beat the Colts.

Indianapolis, with an 8-6 record after a promising start, is seeing its playoff hopes slip away after losing its last four games against the Chiefs, Texans, Jaguars, and Seahawks. The Colts lost a close game 16-18 against Seattle. At 44 years old, incredibly, it's Phillip Rivers who, as quarterback, is leading the Indianapolis offense after Daniel Jones' devastating season-ending injury.

While the age difference between the 49ers' and Colts' quarterbacks is significant, it's also a duel between two of the NFL's best running backs. Jonathan Taylor of the Colts leads the league with 1,443 rushing yards and 18 touchdowns. San Francisco's McCaffrey isn't far behind with 14 touchdowns.

Indianapolis Colts vs San Francisco 49ers Form

Table

Teams Pts P W L
7 San Francisco 49ers
0.706 17 12 5
20 Indianapolis Colts
0.471 17 8 9

Indianapolis Colts and San Francisco 49ers Latest Matches

Indianapolis Colts
Indianapolis Colts Latest matches
L W L L L L
Victories

1/6 (17%)

Defeats

5/6 (83%)

Dec 14, 2025 - NFL

Seattle Seahawks
18 :  16
Indianapolis Colts

Dec 7, 2025 - NFL

Jacksonville Jaguars
36 :  19
Indianapolis Colts

Nov 30, 2025 - NFL

Indianapolis Colts
16 :  20
Houston Texans

Nov 23, 2025 - NFL

Kansas City Chiefs
23 :  20
Indianapolis Colts

Nov 9, 2025 - NFL

Indianapolis Colts
31 :  25
Atlanta Falcons

Nov 2, 2025 - NFL

Pittsburgh Steelers
27 :  20
Indianapolis Colts
W W W W W L
Victories

5/6 (83%)

Defeats

1/6 (17%)

Nov 30, 2025 - NFL

Indianapolis Colts
16 :  20
Houston Texans

Nov 9, 2025 - NFL

Indianapolis Colts
31 :  25
Atlanta Falcons

Oct 26, 2025 - NFL

Indianapolis Colts
38 :  14
Tennessee Titans

Oct 12, 2025 - NFL

Indianapolis Colts
31 :  27
Arizona Cardinals

Oct 5, 2025 - NFL

Indianapolis Colts
40 :  6
Las Vegas Raiders

Sep 14, 2025 - NFL

Indianapolis Colts
29 :  28
Denver Broncos
L W L L L L
Victories

1/6 (17%)

Defeats

5/6 (83%)

Dec 14, 2025 - NFL

Seattle Seahawks
18 :  16
Indianapolis Colts

Dec 7, 2025 - NFL

Jacksonville Jaguars
36 :  19
Indianapolis Colts

Nov 23, 2025 - NFL

Kansas City Chiefs
23 :  20
Indianapolis Colts

Nov 2, 2025 - NFL

Pittsburgh Steelers
27 :  20
Indianapolis Colts

Oct 19, 2025 - NFL

Los Angeles Chargers
24 :  38
Indianapolis Colts

Sep 28, 2025 - NFL

Los Angeles Rams
27 :  20
Indianapolis Colts
San Francisco 49ers
San Francisco 49ers Latest matches
W L W W W W
Victories

5/6 (83%)

Defeats

1/6 (17%)

Dec 14, 2025 - NFL

San Francisco 49ers
37 :  24
Tennessee Titans

Nov 30, 2025 - NFL

Cleveland Browns
8 :  26
San Francisco 49ers

Nov 24, 2025 - NFL

San Francisco 49ers
20 :  9
Carolina Panthers

Nov 16, 2025 - NFL

Arizona Cardinals
22 :  41
San Francisco 49ers

Nov 9, 2025 - NFL

San Francisco 49ers
26 :  42
Los Angeles Rams

Nov 2, 2025 - NFL

New York Giants
24 :  34
San Francisco 49ers
W L W L W W
Victories

4/6 (67%)

Defeats

2/6 (33%)

Dec 14, 2025 - NFL

San Francisco 49ers
37 :  24
Tennessee Titans

Nov 24, 2025 - NFL

San Francisco 49ers
20 :  9
Carolina Panthers

Nov 9, 2025 - NFL

San Francisco 49ers
26 :  42
Los Angeles Rams

Oct 19, 2025 - NFL

San Francisco 49ers
20 :  10
Atlanta Falcons

Sep 28, 2025 - NFL

San Francisco 49ers
21 :  26
Jacksonville Jaguars

Sep 21, 2025 - NFL

San Francisco 49ers
16 :  15
Arizona Cardinals
W L L W W W
Victories

4/6 (67%)

Defeats

2/6 (33%)

Nov 30, 2025 - NFL

Cleveland Browns
8 :  26
San Francisco 49ers

Nov 16, 2025 - NFL

Arizona Cardinals
22 :  41
San Francisco 49ers

Nov 2, 2025 - NFL

New York Giants
24 :  34
San Francisco 49ers

Oct 26, 2025 - NFL

Houston Texans
26 :  15
San Francisco 49ers

Oct 12, 2025 - NFL

Tampa Bay Buccaneers
30 :  19
San Francisco 49ers

Oct 2, 2025 - NFL

Los Angeles Rams
23 :  26
San Francisco 49ers

Indianapolis Colts - San Francisco 49ers Key Points

  1. The Colts have always beaten the 49ers in four meetings since 2009
  2. Philip Rivers threw 27 passes against the Seahawks, completing 18
  3. The 49ers rank fourth in the NFL in passing yards with 246.1
  4. The 49ers' out-and-out record this season is 8-5-1

Our Indianapolis Colts vs San Francisco 49ers Prediction

It seems the momentum for the game at Lucas Oil Stadium belongs entirely to the 49ers. Since Purdy's return, he's not only been in excellent form, but he's also boosted McCaffrey's performance. After their visit to Indianapolis, the Niners will close out the season against the Bears and Seahawks, so a win on Monday would ensure they don't face any last-minute scares in Weeks 17 and 18.

Rivers, 44, looked surprisingly solid in his first snaps in five years; he himself said he's not so much concerned with improving but rather with winning at all costs, given the Colts' desperate need for victories. However, the 49ers' defense could pose a significant challenge for the veteran.

Our prediction for Colts vs 49ers is: 49ers -5.5.

Prediction:

 

49ers -5.5.

-115
$350 offered for betting!

All tips are fully researched and given in good faith, but profits cannot be guaranteed.

Indianapolis Colts vs San Francisco 49ers Picks