Indianapolis, on the other hand, was one of the NFL's powerhouses, featuring a stellar offense with quarterback Peyton Manning and receivers Marvin Harrison and Reggie Wayne.

[9] The Colts wound up winning each of the first nine meetings between the teams, including a 49–14 victory at the RCA Dome in 2004,[10] before Houston finally beat Indianapolis in week 16 of the 2006 season.

Peyton Manning wound up having a 16–2 record against the Texans while with the Colts before being released and signing with the Denver Broncos after sitting out the 2011 season due to injury.

[7] By the second game, both starting quarterbacks had been placed on injured reserve for the teams; in addition to Manning missing the whole season, Texans starter Matt Schaub had been sidelined with a Lisfranc injury, forcing rookie T. J. Yates to play in his stead.

The Colts then obtained the first overall pick in the 2012 NFL draft, which they then used to select Stanford quarterback and Houston native Andrew Luck to fill in the void left by Manning.

[16] Despite the growing animosity between the two teams, many players and executives from the Colts organization helped the Texans with donations and fundraising in the aftermath of Hurricane Harvey at the start of the 2017 season.

The Colts won the game thanks to effective play from Luck, running back Marlon Mack, and their defense, keeping Houston scoreless until the fourth quarter with a 21–7 win.

[19][20][7] In 2019, the Texans and Colts were both in position to contend for the AFC South title, despite Indianapolis losing Andrew Luck to a sudden retirement prior to the season.

The two teams met in week 1 of the 2022 season, with Matt Ryan now under center for Indianapolis and Davis Mills entering his second year as the Texans' starting quarterback.