The season is notable for Buffalo's first playoff game in this year, known as "The Comeback", in which the Bills, down 35–3, ended up winning in overtime. The game has since gone down in NFL lore. The game was the first of three Buffalo playoff wins (the two others were at Pittsburgh and at Miami) that allowed the Bills to win their third consecutive AFC Championship. In Super Bowl XXVII, Dallas beat Buffalo, 52–17.
In Week Two of the season, the Bills traveled to San Francisco, defeating the 49ers 34–31. The matchup was notable for being the first game in NFL history without a punt by either team.
Hosting the L.A. Rams, the Bills picked off Jim Everett four times and limited the Rams to 215 total yards. Thurman Thomas led a 207-yard rushing attack for the Bills as Jim Kelly needed only 106 passing yards and two scores for the 40–7 win.
The Jets hosted the Bills in a back-and-forth affair. The Bills led 17–13 in the fourth before Brad Baxter ran in a one-yard score, but Kelly led the Bills downfield and found Thurman Thomas from twelve yards out and the 24–20 Bills win.
The Patriots traveled to Rich Stadium and the two teams managed six turnovers and just 484 total yards. The Bills fell behind 7–0 on Vincent Brown's 25-yard fumble return score, then scored 16 unanswered points on two touchdowns and a safety when Shawn McCarthy was downed in the endzone.
The Bills fell to the Jets 24–17 in a game the Jets needed far more than the Bills following a paralyzing injury to Dennis Byrd; the Jets had needed emotional counseling all week leading to the game, and came out inspired when coach Bruce Coslet told players beforehand that Byrd was recovering movement. Brad Baxter ran in two touchdowns; after the Bills tied the game 17–17 Brian Washington intercepted Kelly and scored. Following the 24–17 Jets win, both teams met at midfield in prayer for Dennis Byrd.
At the Astrodome Jim Kelly was intercepted once and injured in the final game of the season, forcing Frank Reich to take over as starting quarterback to begin the playoffs. Reich was picked off twice as the Oilers behind Warren Moon and Cody Carlson stormed to a 27–3 win, securing a wildcard playoff berth, where one week later they would travel to Buffalo to face Reich again.
In the playoffs following the 1992 season against the Houston Oilers. Reich led the Bills on a 35–3 run in the second half before overtime, en route to a 41–38 victory on a Steve Christie field goal. Reich would help the Bills defeat the Pittsburgh Steelers in the divisional round before once again giving the team back to Kelly, who led them into Super Bowl XXVII, where they were annihilated by the Dallas Cowboys 52–17. Reich had to enter the game when starter Jim Kelly was forced out of the game with a knee injury during the 2nd quarter.
The Bills entered Super Bowl XXVII trying to avoid becoming the first team to lose three consecutive Super Bowls. Once again the team was loaded with talent, boasting 12 Pro Bowl selections. During the regular season, Buffalo's no-huddle offense ranked as the number two offense in the league (6,114 yards) and ranked as the number one rushing offense (2,436). Running back Thurman Thomas rushed for 1,487 yards and 9 touchdowns during the regular season, while also catching 58 passes for 626 yards and another 3 touchdowns. Running back Kenneth Davis rushed for 613 yards, caught 15 passes for 80 yards, and added another 251 yards returning kickoffs. Quarterback Jim Kelly had 269 out of 462 completions for 3,457 yards, 23 touchdowns, and 19 interceptions. Wide receiver Andre Reed lead the team with 65 receptions for 913 yards and 3 touchdowns, receiver James Lofton contributed 51 receptions for 786 yards and 6 touchdowns, and wide receiver Don Beebe had 33 receptions for 554 and 2 touchdowns. Also tight end Pete Metzelaars recorded 30 receptions for 298 yards and 6 touchdowns. The Bills also had one of the best offensive lines in the NFL, led by Pro Bowlers Will Wolford, Jim Ritcher, and Howard Ballard, along with center Kent Hull.
On defense, the line was anchored by tackles Bruce Smith (14 sacks) and Jeff Wright (6 sacks, 1 fumble recovery), who were fully recovered after missing almost all of the previous season due to injuries. The Bills were once again led by their trio of linebackers Darryl Talley (77 tackles, 4 sacks), Shane Conlan (66 tackles, 2 sacks, 1 interception), and Pro Bowler Cornelius Bennett (52 tackles, 4 sacks, 3 fumble recoveries). The defensive secondary was aided by the emergence of second year defensive back Henry Jones, who led the NFL with 8 interceptions, returning them for 263 yards and 2 touchdowns. Defensive back Mark Kelso recorded 7 interceptions, while Pro Bowl defensive back Nate Odomes had 5.
However, the Bills quest for a third consecutive Super Bowl suffered a major setback when they lost the final game of the season to the Houston Oilers. The loss caused the Bills to finish with an 11–5 record, losing the AFC East title to the Miami Dolphins based on tiebreaking rules, and thus making them a wild card team for the playoffs. Thus, even if they won their first playoff game, they would have to win two on the road to make the Super Bowl. To make matters worse, Kelly also suffered strained knee ligaments during the loss to the Oilers and had to miss the first 2 playoff games. Furthermore, their first opponent in the playoffs ended up being the Oilers. A headline on a Buffalo newspaper stated the Bills situation: "Bills Begin The Longest Road Today."