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

USA - NFL

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

Prediction:

 

49ers -5.5.

-115
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 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.

San Francisco 49ers vs Indianapolis Colts Form

Table

Teams % P W D L
9
San Francisco 49ers
San Francisco 49ers
0.714 14 10 0 4
14
Indianapolis Colts
Indianapolis Colts
0.571 14 8 0 6

San Francisco 49ers and Indianapolis Colts Latest Matches

San Francisco 49ers
San Francisco 49ers Latest matches
W L W W W W
Victories

5/6 (83%)

Draw

0/6 (0%)

Defeats

1/6 (17%)

Dec 14, 2025 - NFL

Tennessee Titans
24 :  37
San Francisco 49ers

Nov 30, 2025 - NFL

San Francisco 49ers
26 :  8
Cleveland Browns

Nov 24, 2025 - NFL

Carolina Panthers
9 :  20
San Francisco 49ers

Nov 16, 2025 - NFL

San Francisco 49ers
41 :  22
Arizona Cardinals

Nov 9, 2025 - NFL

Los Angeles Rams
42 :  26
San Francisco 49ers

Nov 2, 2025 - NFL

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

4/6 (67%)

Draw

0/6 (0%)

Defeats

2/6 (33%)

Dec 14, 2025 - NFL

Tennessee Titans
24 :  37
San Francisco 49ers

Nov 24, 2025 - NFL

Carolina Panthers
9 :  20
San Francisco 49ers

Nov 9, 2025 - NFL

Los Angeles Rams
42 :  26
San Francisco 49ers

Oct 19, 2025 - NFL

Atlanta Falcons
10 :  20
San Francisco 49ers

Sep 28, 2025 - NFL

Jacksonville Jaguars
26 :  21
San Francisco 49ers

Sep 21, 2025 - NFL

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

4/6 (67%)

Draw

0/6 (0%)

Defeats

2/6 (33%)

Nov 30, 2025 - NFL

San Francisco 49ers
26 :  8
Cleveland Browns

Nov 16, 2025 - NFL

San Francisco 49ers
41 :  22
Arizona Cardinals

Nov 2, 2025 - NFL

San Francisco 49ers
34 :  24
New York Giants

Oct 26, 2025 - NFL

San Francisco 49ers
15 :  26
Houston Texans

Oct 12, 2025 - NFL

San Francisco 49ers
19 :  30
Tampa Bay Buccaneers

Oct 2, 2025 - NFL

San Francisco 49ers
26 :  23
Los Angeles Rams
Indianapolis Colts
Indianapolis Colts Latest matches
L W L L L L
Victories

1/6 (17%)

Draw

0/6 (0%)

Defeats

5/6 (83%)

Dec 14, 2025 - NFL

Indianapolis Colts
16 :  18
Seattle Seahawks

Dec 7, 2025 - NFL

Indianapolis Colts
19 :  36
Jacksonville Jaguars

Nov 30, 2025 - NFL

Houston Texans
20 :  16
Indianapolis Colts

Nov 23, 2025 - NFL

Indianapolis Colts
20 :  23
Kansas City Chiefs

Nov 9, 2025 - NFL

Atlanta Falcons
25 :  31
Indianapolis Colts

Nov 2, 2025 - NFL

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

5/6 (83%)

Draw

0/6 (0%)

Defeats

1/6 (17%)

Nov 30, 2025 - NFL

Houston Texans
20 :  16
Indianapolis Colts

Nov 9, 2025 - NFL

Atlanta Falcons
25 :  31
Indianapolis Colts

Oct 26, 2025 - NFL

Tennessee Titans
14 :  38
Indianapolis Colts

Oct 12, 2025 - NFL

Arizona Cardinals
27 :  31
Indianapolis Colts

Oct 5, 2025 - NFL

Las Vegas Raiders
6 :  40
Indianapolis Colts

Sep 14, 2025 - NFL

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

1/6 (17%)

Draw

0/6 (0%)

Defeats

5/6 (83%)

Dec 14, 2025 - NFL

Indianapolis Colts
16 :  18
Seattle Seahawks

Dec 7, 2025 - NFL

Indianapolis Colts
19 :  36
Jacksonville Jaguars

Nov 23, 2025 - NFL

Indianapolis Colts
20 :  23
Kansas City Chiefs

Nov 2, 2025 - NFL

Indianapolis Colts
20 :  27
Pittsburgh Steelers

Oct 19, 2025 - NFL

Indianapolis Colts
38 :  24
Los Angeles Chargers

Sep 28, 2025 - NFL

Indianapolis Colts
20 :  27
Los Angeles Rams

San Francisco 49ers - Indianapolis Colts 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 San Francisco 49ers vs Indianapolis Colts 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
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San Francisco 49ers vs Indianapolis Colts Picks