After the Patriots parted ways with longtime head coach Bill Belichick at the end of the 2023 season, O'Brien was not retained by the team.

In 2012, O'Brien was hired by Penn State to take over a program that had just endured a child sexual abuse scandal perpetrated by one of its coaches.

After the 2012 season, he garnered significant interest to return to the National Football League (NFL) as a head coach and interviewed with both the Philadelphia Eagles and the Cleveland Browns.

However, O'Brien decided to stay at Penn State, citing that it would send a poor message to leave after just one season.

[3][4][5] O'Brien's tenure with the Texans included a 51–31 Divisional Round loss to the eventual Super Bowl winning Kansas City Chiefs team after leading 24–0 in the second quarter, and a controversial trade of star wide receiver DeAndre Hopkins to the Arizona Cardinals.

In light of these NCAA sanctions, O'Brien issued the following statement: "Today we receive a very harsh penalty from the NCAA and as head coach of the Nittany Lions football program, I will do everything in my power to not only comply, but help guide the University forward to become a national leader in ethics, compliance and operational excellence.

[24] In O'Brien's first game as Penn State's head coach, the Nittany Lions lost to the Ohio University Bobcats by a score of 24–14.

Despite the fallout from the Jerry Sandusky scandal, O'Brien's first season as coach at Penn State was far more successful than anticipated and resulted in a final record of 8–4.

"[31] After Houston Texans head coach Gary Kubiak was fired on December 6, 2013, multiple reports stated that O'Brien was interested in returning to the NFL.

[32] The Texans had finished 2–14 in 2013 and owned the first overall selection in the 2014 NFL draft, which they used on South Carolina defensive end Jadeveon Clowney.

[33] O'Brien earned his first win as a head coach when the Texans beat the Washington Redskins in the season-opener by a score of 17–6.

[40] The 2017 season marked O'Brien's first as an NFL head coach in which his team did not finish with a winning record.

[41] The 2017 season saw the debut of quarterback Deshaun Watson, whom the Texans selected in the first round with the 12th overall pick in the 2017 NFL draft.

[42] However, Watson's season prematurely ended after he tore his ACL in practice prior to Week 9,[43][44] which along with injuries to various other players contributed to the team's collapse.

[46] The Texans started the season 0–3, but then went on a nine-game winning streak and finished atop the AFC South with an 11–5 record.

[49] The Texans outlasted the Buffalo Bills in the Wild Card Round with a 22–19 overtime victory, overcoming a 16–0 halftime deficit.

[50] However, they were eliminated in the Divisional Round with a 51–31 road loss to the eventual Super Bowl LIV champion Kansas City Chiefs despite a 24–0 lead in the second quarter.

O’Brien's offensive unit during the 2021 season was led by quarterback Bryce Young, who set the school record for most passing yards in a single game (559) and won several Player of the Year awards in 2021, including the Heisman Trophy.

[58] However, he received significant criticism from fans during his tenure at Alabama due to the teams’ inability to win a National Championship, as well as a lack of player development at the quarterback position, despite Young winning the Heisman and being drafted first overall in the 2023 NFL Draft by the Carolina Panthers.

[64] He never coached a practice or game for the Buckeyes, as O'Brien departed for Boston College just a few weeks after the initial hiring.

On February 9, 2024, O'Brien was hired as the head coach of Boston College, replacing Jeff Hafley, who left to become the defensive coordinator of the Green Bay Packers.