Indianapolis Colts vs Los Angeles Rams Prediction, Odds and Picks for Today, 09/28/25

The expectations heading into the season on the Colts were grim as the quarterback preseason battle came down to Anthony Richardson and Daniel Jones. After Richardson suffered an injury in the first exhibition contest, Jones was inserted and solidified the starting position. Following a rocky tenure with the Giants, Jones has led the Colts to a 3-0 record and the lead atop the AFC South. Indianapolis grabbed a pair of home victories over Miami and Denver before routing Tennessee last week, 41-20, as 6-point road favorites. Colts RB Jonathan Taylor leads the NFL in rushing with 338 yards and scored 3 touchdowns in the blowout of the Titans.

The Rams return home after a crushing loss at Philadelphia last week, blowing a 26-7 advantage in a 33-26 defeat. We all know the devastating point-spread loss on Los Angeles, which was receiving 3.5 points but allowed Philadelphia to return the last-second blocked field goal for a touchdown and the cover. Los Angeles is already playing its 3rd game against an AFC South opponent, beating Houston and Tennessee in the first 2 weeks. The Rams allowed 28 points in those victories and yielded 7 points in the first half against the Eagles. However, Philadelphia dropped 26 points in the 2nd half, marking its second victory over LA since the divisional playoffs in January.

The Colts have faced 3 teams that rank in the bottom half of the NFL in yards per game, but take on a Rams squad that sits 5th in the league at 363.7 yards per contest. On the flip side, LA has seen 3 teams that rank in the bottom 6 of the NFL in yardage. The Rams are 3-1 in their last 4 games as a home favorite since the start of 2024. The Colts are in the midst of a 2-4 SU and 4-2 ATS stretch in their past 6 opportunities as a road underdog. Since 2013, 3-0 teams listed as road underdogs have slumped to a 3-11 ATS mark, which includes 10 losses by 8 points or more. With that in mind, I like the Rams to get back on track here and to hand Indianapolis their first loss of the season.

Colts vs Rams prediction: Rams -3.5 (-110) available at time of publishing. Playable to 4.

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