He attended Timber Point Elementary and East Islip High School, where he graduated in 1979. In high school, he was a three-sport varsity player in football, basketball, and baseball.

Esiason played college football at the University of Maryland for head coaches Jerry Claiborne and Bobby Ross and offensive coordinator Ralph Friedgen. Maryland was the only college to offer him a scholarship. At Maryland, he set 17 school records. He completed 461 of 850 passes (54.2 percent) for 6,169 yards and 42 touchdowns with 27 interceptions. He was a two-time honorable mention All-American in 1982 and 1983. In his final home game, he threw two third-quarter touchdown passes to lead a comeback victory over No. 3 North Carolina and seal the ACC title. He graduated with a B.A. in 1984 and received the Distinguished Alumnus Award in 1999.

He got his first pro start on October 7, 1984, in Cincinnati in a game against the Houston Oilers. On a rainy day, he led the Bengals to a 13–3 win over Houston and scored the game’s only touchdown on a three-yard run. He took over for Ken Anderson as the Bengals’ full-time starting quarterback on September 22, 1985, in a loss in Cincinnati to the San Diego Chargers and future Hall of Famer Dan Fouts 44–41, becoming the signal caller on what was to become one of the most potent offenses of the late 1980s. He became particularly adept at running the difficult “no huddle” offense devised by Bengal Head Coach Sam Wyche.

On December 21, 1986, the final game of the 1986 season, he set a team record by throwing five touchdown passes as Cincinnati shot down the New York Jets 52–21. He also set the team single season passing record of 3,959 yards in this game. It was the last game of Bengals’ quarterback Ken Anderson’s playing career.

In 1986, Esiason married his wife, Cheryl. They have two children, son Gunnar and daughter Sydney. Sydney is married to New York Islanders forward Matt Martin. While at a Jets mini-camp in 1993, Esiason was notified that two-year-old Gunnar had to be taken to the hospital with breathing difficulties. Soon after, Gunnar was diagnosed with cystic fibrosis. Gunnar is a graduate of Boston College who undergoes daily treatments and takes cystic fibrosis medications. He was a quarterback for his high school football team at Friends Academy in Locust Valley, NY, and played forward on his ice hockey team for the Manhasset/Roslyn varsity hockey team. Gunnar also writes a popular blog and appears daily in a podcast discussing the issues confronting cystic fibrosis patients.

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.

On October 29, 1989, he tied his own record for touchdown passes in a game as the Bengals demolished the Tampa Bay Buccaneers 56–23. The Bengals tied a team record with eight touchdowns in the game.

He made two appearances on the game show Family Feud. On March 18, 1989, he appeared in the episode “Bengals v. 49ers”, reminiscent of their latest Super Bowl match. In 1993, his second Family Feud appearance came in the episode “NFC v. AFC”.

On October 7, 1990, he threw for 490 yards (a single game team passing record) in a 34-31 victory over the Los Angeles Rams.

Esiason, who had worked with Jets head coach Bruce Coslet in Cincinnati, was traded to the Jets for a third round pick in 1993 (which became linebacker Steve Tovar), subsequently guiding their offense until the end of 1995 under three different head coaches: Coslet, Pete Carroll, and Rich Kotite. During his 1995 season with the Jets, he was seriously injured in a game played on October 8 against the Buffalo Bills when rookie Everett McIver was whistled for a false start and Bruce Smith of the Bills raced around him and caught Esiason under his face mask. Smith was terribly upset about Esiason’s injury and said he never heard a whistle blowing the play dead for false start. That horrific collision gave Esiason a severe concussion, which kept him out until November 19. He is thought to have been the first NFL player to enter a concussion study during the season. When he returned to the field it was coincidentally in a game that was played against the Bills.

He authored a children’s reader in 1995 titled A Boy Named Boomer and co-wrote (with Lowell Cauffiel) a 1998 novel titled Toss.

After being released by the Jets, Esiason signed with the Arizona Cardinals as a free agent in 1996. It was during this season, on November 10, 1996, that he threw for the fourth best passing yardage day in NFL history, with 522 yards in a 37–34 overtime victory over the Washington Redskins. Two weeks later he led a fourth-quarter comeback against the playoff-bound Eagles.

In 1996, Esiason formed a partnership with Cantor Fitzgerald and Howard Lutnick (CEO) as the foundation offices were moved to the North Tower of the World Trade Center in lower Manhattan on the 101st floor, which was destroyed in 2001 in the September 11 attacks. All five full-time employees survived, as none were in the building at the time, but “Esiason figured he knew over 200 people personally” who were killed in the attack, including his best friend Tim O’Brien who was a partner at Cantor.

On December 21, 1997, he played his last NFL game. His last play was a 79-yard touchdown play-action pass to wide receiver Darnay Scott. The touchdown proved to be the winner in a 16–14 victory over the Baltimore Ravens.

At his retirement in 1997 Esiason was among the most successful quarterbacks in NFL history, finishing in the top 10 in many statistical categories. At 6′-5″ and 224 pounds with a powerful arm, he was surprisingly mobile, rushing for 1,598 yards on 447 attempts and scoring seven touchdowns in his career.

He co-hosted the Miss America Pageant with Meredith Vieira on September 19, 1998, and co-hosted with Julie Chen the CBS broadcast of the 2002 Macy’s Thanksgiving Day Parade.

While still playing, Esiason appeared as a color analyst on the USA Network’s two-year broadcast of the World League of American Football (WLAF) on Monday nights, partnered with Brad Nessler. After his retirement from playing, he went into broadcasting full-time. He was a color commentator for ABC’s Monday Night Football from 1998 to 1999. Following his dismissal by ABC (due primarily to personal conflicts between him and play-by-play announcer Al Michaels), he was hired by the Westwood One radio network to become the lead analyst for radio broadcasts of Monday Night Football and Super Bowl games. He broadcast every Super Bowl from SB XXXIV in 2000 to SB LII in 2018, a total of 19, which is a broadcast record. As planned, after broadcasting the Thursday night football game on September 6, 2018, he left Westwood One. He was quoted as saying “I’m going to miss it, but in all reality I kind of have to get part of my life back.” He currently serves as an in-studio analyst for The NFL Today on CBS television, Inside the NFL on Showtime, and hosts Boomer and Gio on WFAN Radio in New York and the CBS Sports Network. In September 2012, CBS Radio announced he was added to their collection of talent to deliver five sports updates per day Monday through Friday.

Esiason was inducted into the Suffolk Sports Hall of Fame in the Football Category with the Class of 1990. In 2004, he was inducted into the Nassau County Sports Hall of Fame.

In April 2007, after the firing of Don Imus, CBS Radio gave Esiason a one-week “try-out” as Imus’ replacement on WFAN. The station announced him as the permanent host on August 13, with radio veteran Craig Carton joining as co-host. Boomer and Carton officially started on September 4, 2007. As an analyst with Westwood One, Esiason would do the Monday morning show, travel to do the Monday Night Football game and travel back to New York in time to do the Tuesday morning show. The Boomer and Carton radio program became the number-one rated morning show in all key demographics in the greater N.Y. listening area and was seen on the CBSN/TV Network from 2010–2013. On March 8, 2013, both Esiason and Carton worked the radio broadcast of a Brooklyn Nets basketball game. The radio program had been simulcast on the CBS Sports Network since January 2014. In September 2017, after being arrested and facing charges of operating a concert ticket Ponzi scheme, Carton resigned from WFAN, leaving Esiason as the sole host of the show, which was rebranded The Morning Show with Boomer. On January 2, 2018, the show became Boomer and Gio, when Gregg Giannotti joined him as a permanent co-host.

Starting in 2013, he began appearing once a week as a guest on The Jim Rome Show during the NFL season to break down the upcoming weekend’s NFL action.

In 2015, he became the Commissioner of the FFL (Feline Football League) for Kitten Bowl II on the Hallmark Channel, and still holds that position today. He has provided analysis and commentary for all the Kitten Bowls since Kitten Bowl II, which airs during half time of the Super Bowl.

The Boomer Esiason Foundation (BEF) was formed soon after Gunnar’s diagnosis to fund research to find a cure for cystic fibrosis. The foundation also provides scholarships, transplant grants, hospital grants, and education and awareness of CF to help provide a higher quality of life for people with CF. The foundation has raised in excess of $100 million, and has supported numerous hospitals, including Cincinnati Children’s Hospital with the Gunnar H Esiason CF/Lung Center and Columbia Presbyterian in NYC with the Gunnar H Esiason Adult CF and Lung Program. In 2018 the foundation awarded over $400,000 in scholarships to almost 100 students. The foundation is located in New York City and runs numerous events around the country. The foundation annually receives four stars from Charity Navigator.