With the New England Patriots as the defending league champions, regular season play was held from September 9, 2004 to January 2, 2005. Hurricanes forced the rescheduling of two Miami Dolphins home games: the game against the Tennessee Titans was moved up one day to Saturday, September 11 to avoid oncoming Hurricane Ivan, while the game versus the Pittsburgh Steelers on Sunday, September 26 was moved back 7½ hours to miss the eye of Hurricane Jeanne.
Due to several incidents during the 2003 NFL season, officials are authorized to penalize excessive celebration. The 15-yard unsportsmanlike conduct penalty will be marked off from the spot at the end of the previous play or, after a score, on the ensuing kickoff. If the infraction is ruled flagrant by the officials, the player can be ejected.
Due to several instances during the 2003–04 playoffs, officials are instructed to strictly enforce illegal contact, pass interference, and defensive holding.
Timeouts can be called by head coaches.
In addition to the numbers 80–89, wide receivers will now be allowed to use numbers 10–19.
A punt or missed field goal that is untouched by the receiving team is immediately dead once it touches either the end zone or any member of the kicking team in the end zone. Previously, a punt or missed field goal that lands in the end zone before being controlled by the kicking team could be picked up by a member of the receiving team and immediately run the other way.
Teams will be awarded a third instant replay challenge if their first two are successful. Previously, teams were only limited to two regardless of what occurred during the game.
The Colts led the NFL with 522 points scored. The Colts tallied more points in the first half of each of their games of the 2004 NFL season (277 points) than seven other NFL teams managed in the entire season.  Despite throwing for 49 touchdown passes, Peyton Manning attempted fewer than 500 passes for the first time in his NFL career.