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Regular season

Currently, the 14 opponents each team faces over the 17-game regular season schedule are set using a pre-determined formula: The league runs an 18-week, 272-game regular season. Since 2021, the season has begun the week after Labor Day (the first Monday in September) and concluded the week after New Year. The opening game of the season is normally a home game on a Thursday for the league's defending champion.

Most NFL games are played on Sundays, with a Monday night game typically held at least once a week and Thursday night games occurring on most weeks as well. NFL games are not normally played on Fridays or Saturdays until late in the regular season, as federal law prohibits professional football leagues from competing with college or high school football. Because high school and college teams typically play games on Friday and Saturday, respectively, the NFL cannot hold games on those days until the Friday before the third Saturday in December. While Saturday games late in the season are common, the league rarely holds Friday games, the most recent one being on Christmas Day in 2020. NFL games are rarely scheduled for Tuesday or Wednesday, and those days have only been used three times since 1948: in 2010, when a Sunday game was rescheduled to Tuesday due to a blizzard; in 2012, when the Kickoff game was moved from Thursday to Wednesday to avoid conflict with the Democratic National Convention; and in 2020, when a game was postponed from Sunday to Tuesday due to players testing positive for COVID-19.

NFL regular season matchups are determined according to a scheduling formula. Within a division, all four teams play 14 out of their 17 games against common opponents or each other– two games (home and away) are played against the other three teams in the division, while one game is held against all the members of a division from the NFC and a division from the AFC as determined by a rotating cycle (three years for the conference the team is in, and four years in the conference they are not in). Two of the other games are intraconference games, determined by the standings of the previous year – for example, if a team finishes first in its division, it will play two other first-place teams in its conference, while a team that finishes last would play two other last-place teams in the conference. The final game is an inter-conference based on a rotating cycle and determined by previous season's standings. In total, each team plays 17 games and has one bye week, where it does not play a game.

Although a team's home and away opponents are known by the end of the previous year's regular season, the exact dates and times for NFL games are not determined until much later because the league has to account for, among other things, the Major League Baseball postseason and local events that could pose a scheduling conflict with NFL games. During the 2010 season, over 500,000 potential schedules were created by computers, 5,000 of which were considered "playable schedules" and were reviewed by the NFL's scheduling team. After arriving at what they felt was the best schedule out of the group, nearly 50 more potential schedules were developed to try to ensure that the chosen schedule would be the best possible one.