After leading Cincinnati to six straight wins to begin the 1988 season, on October 16, 1988 he set a single game team record throwing 5 interceptions in a 27–21 loss to the New England Patriots. The team finished the season 12–4 with the highest scoring offense in the NFL, securing the organization's fifth AFC Central division title. He finished the season as the NFL's top rated passer. Cincinnati defeated Seattle and then Buffalo in the playoffs to reach Super Bowl XXIII, their second appearance in a Super Bowl, a rematch with the San Francisco 49ers. In the game, Bengals cornerback Lewis Billups dropped a sure interception in the end zone which would have sealed a Cincinnati win. The San Francisco 49ers, led by future Hall of Fame quarterback Joe Montana, marched 92 yards on their last drive and scored on a touchdown pass to receiver John Taylor with 34 seconds remaining in the game. A last-ditch pass by Esiason to wide receiver Cris Collinsworth was broken up, resulting in a 20–16 loss for the Bengals, their second close loss to the 49ers in a Super Bowl.
Esiason was named to four Pro Bowl games (1986, 1988, 1989, 1993) and holds several NFL career records for left-handed quarterbacks, including most touchdown passes (247), passing yards (37,920), and completions (2,969). He also led the AFC in passing in both 1988 and 1989.
Among the awards he has earned during his career include the NFL Most Valuable Player Award in 1988 (leading the league with a passer rating of 97.4), and the Walter Payton Man of the Year Award in 1995 for his charitable work. At his retirement in 1997 he finished in the top 10 all-time in many QB career statistical categories. In addition, he is the only quarterback to hold a franchise record in single game passing yards with two different teams, having thrown for 522 yards with the Arizona Cardinals on November 10, 1996 and 490 yards for the Cincinnati Bengals on October 7, 1990.