Hoyer's longest stint has been with the New England Patriots for eight non-consecutive seasons, primarily as a backup, and he was a member of the team that won Super Bowl LIII.

He was the winning pitcher in the 2002 Ohio Division I State Championship game allowing 2 earned runs in 6 innings pitched.

He was named USA Today Prep Player of the Week for his performance against Shaker Heights High School.

[4] Hoyer was redshirted by Michigan State University in 2004, where he earned Scout Team Offensive Player of the Week honors twice.

[5] In a game against Illinois, he combined with Drew Stanton to throw seven touchdown passes, which tied the Big Ten single-game record.

[13] In the preseason finale against the New York Giants, he played at quarterback the entire game, leading the team on a comeback after trailing 21–0 in the first quarter to a 38–27 win, completing 18-of-25 passes for 242 yards, one touchdown, and no interceptions.

On his first drive, he was 5-for-5 for 35 yards, concluding it with a 1-yard rushing touchdown, which set a franchise record for points scored in the Patriots' 59–0 win.

[19][20] In the playoffs, the Patriots defeated the Denver Broncos in the Divisional Round and the Baltimore Ravens in the AFC Championship Game to reach Super Bowl XLVI.

[25] On November 20, 2012, Hoyer signed with the Pittsburgh Steelers after injuries to starting quarterback Ben Roethlisberger and backup Byron Leftwich within a week of each other.

[32] On September 18, in relief of then-starter Brandon Weeden, who was out with a thumb injury, the Browns skipped over second string Jason Campbell and named Hoyer the starting quarterback for the Week 3 game against the Minnesota Vikings.

[34] The next day on September 30, Hoyer was named the starter for a third straight game, Thursday Night Football vs the Buffalo Bills.

However, Hoyer sustained an ACL tear in the Thursday Night game versus the Buffalo Bills, ending his promising season.

Head Coach Mike Pettine stated that Manziel would not simply be handed the job, leaving the starter position open to competition.

[38] Through the first six weeks the Browns were 3–2, with the two losses coming on last-second scores, and Hoyer possessing a 7–1 TD:INT ratio.

Hoyer's struggles in this 1–3 stretch led many fans, pundits, and analysts to call for the quarterback to be benched in favor of rookie Johnny Manziel.

In the first game of the 2015 season, with Houston trailing to the Kansas City Chiefs 27–9, Hoyer was benched in the fourth quarter in favor of Mallett.

[46] On September 17, head coach Bill O'Brien announced that Hoyer would be benched in favor of Mallett for the second game of the season against the Panthers.

The Texans played in the first Wild Card Round against the Kansas City Chiefs, where Hoyer struggled, throwing for 136 passing yards and four interceptions.

[58] Hoyer is tied for the most 300-yard passing games by a Bears quarterback in a single season with 4, alongside Cutler, Mitchell Trubisky, Caleb Williams and Billy Wade.

[61] During Hoyer's sixth start in Week 6 against the Washington Redskins, he was benched in favor of rookie C. J. Beathard during the second quarter after completing 4 of 11 passes for 34 yards.

[63] It was also reported that Hoyer was originally part of the trade, but the Patriots did not want him included due to compensatory draft pick reasons.

[64][65] On November 1, 2017, Hoyer signed a three-year contract to return to the Patriots to be the backup to Tom Brady, with whom he started his career.

[67] In the regular season finale on December 31, Hoyer was brought in to end the game after the Patriots led the New York Jets by 20 points.

[76] He came into the game on November 3 in place of an injured Jacoby Brissett and threw for 168 yards, three touchdowns, and an interception in the 26–24 loss against the Steelers.

[81] After Newton tested positive for COVID-19 prior to a Week 4 matchup against the Chiefs, Hoyer became the Patriots' starter for the first time in his career.

Hoyer struggled during the game, committing two red zone miscues that stopped the Patriots from scoring – a sack preventing New England from running another play before the first half ended and a fumble recovered by the Chiefs.

[84] On August 31, 2021, Hoyer was released from the Patriots during final roster cuts,[85] but signed with the practice squad the following day.

During a Week 7 rout of the Jets, Hoyer made his season debut when he relieved Jones in the fourth quarter.

[88] Hoyer made his third relief appearance during Week 17 against the Jaguars, throwing for 63 yards in the fourth quarter and completing the 50–10 rout by taking the victory formation.

[97] In Week 7, Brian Hoyer was selected to start his first game for the Raiders against the Bears over newly-acquired fourth round quarterback Aidan O'Connell.