Roethlisberger, Rivers, and Manning have all been voted to the Pro Bowl since becoming starters. Roethlisberger and Manning have each won two Super Bowls. The trio have been compared favorably to the Quarterback class of 1983, which included Hall of Fame quarterbacks Dan Marino, John Elway, and Jim Kelly.

Roethlisberger has been one of the most efficient passers in NFL history. He currently ranks 9th all-time in NFL passer rating (94.0), tied for 6th in yards per attempt (7.93), and tied for 10th in completion percentage (63.85%) among quarterbacks with a minimum of 1,500 career attempts. He has the fourth highest career winning percentage (.710) as a starter in the regular season among quarterbacks with a minimum of 100 starts. He is one of six quarterbacks in NFL history to have beaten at least 31 of the current NFL teams.

Roethlisberger played college quarterback at Miami University in Oxford, Ohio. After arriving at Miami in 2000, he was redshirted his first season. In the 2001 season, he made his collegiate debut against Michigan, completing 18 of 35 passes for 193 yards and 2 touchdowns. Against Akron, he broke the school single-game passing record with 399 passing yards, with 70 of those yards coming on a Hail Mary to Eddie Tillitz to win as time expired. When Miami played Bowling Green, he had 2 touchdowns and 305 passing yards and broke the MAC freshman passing yardage record. Playing against Hawai'i he broke school records for attempts, completions, and yardage, when he went 40 of 53 for 452 yards. He finished his first year with the Redhawks with 3,105 passing yards, 241 completions, and 25 touchdown completions.

Roethlisberger started the 2002 regular season opener on August 31 against North Carolina, throwing for 204 yards and having a career best 59-yard punt. Against Iowa, on September 7, he threw for 343 yards and 3 touchdowns in a disappointing Miami loss. He broke the MAC single-game record for passing yards in a loss against Northern Illinois on October 12, 2002 when he threw for 525 yards and 4 touchdowns. He won the MAC East Special Teams Player of the Week for three punts that landed inside the 20 against Toledo. He established the Miami single-season record with 3,238 passing yards and 271 completions in 2002.

The success of the 2003 Miami Redhawks led to the expectation that Roethlisberger would be drafted early. During the GMAC Bowl, commentators discussed some of his skills that would translate to success in the NFL.

Roethlisberger set an NFL rookie record in 2004 with five comeback wins in the fourth quarter, and six game-winning drives in the fourth quarter/overtime (including one playoff game). Roethlisberger has the most comeback wins (19) and game-winning drives (25) through the first seven seasons of a player's career. He is the only quarterback in NFL history to reach 20 comeback wins before the age of 30.

In the wake of Kellen Winslow II's crashing of his motorcycle in May 2005, Roethlisberger had been criticized by various NFL members and the media for not wearing a helmet while riding. Even Roethlisberger's coach, Bill Cowher, lectured him about motorcycle safety. Former Steeler Terry Bradshaw warned Roethlisberger personally when he visited the Steelers' training camp at Saint Vincent College in Latrobe, Pennsylvania, and on television, saying, "Ride it when you retire." In a segment put together by ESPN following Winslow's accident, Roethlisberger had said he did not wear a helmet because it was not required by law, adding, "You're just more free when you're out there and there's no helmet on." Transcripts of the interview recall Roethlisberger telling Suzy Kolber that he only rides a Harley, or his chopper with friends, not a sport bike (like the one Winslow was on). He also claimed to have his license. Both statements have been proven false since the accident.

He has appeared on the Late Show with David Letterman, after both of his Super Bowl victories. At the 2006 Grammy Awards, one week after Pittsburgh won Super Bowl XL, Roethlisberger introduced Kelly Clarkson. In 2009, he hosted WWE Raw. He, along with other Steelers players, made a cameo appearance as a member of the Gotham Rogues football team, in the 2012 film The Dark Knight Rises.

Roethlisberger threw his 29th touchdown pass of the season in Week 15 against the Jaguars, breaking the team single-season touchdown pass record previously held by Bradshaw. On Thursday Night Football against the Rams in Week 16, Roethlisberger became the first quarterback in NFL history to have two perfect passer rating (158.3) games in the same regular season, completing 16 of 20 passes for 261 yards and 3 touchdowns. It was his third career perfect passer rating game, tying Peyton Manning for the most such regular season games in NFL history. He earned his second AFC Offensive Player of the Week nod for the 2007 season.

According to the affidavit, defendant Antonetti claimed that McNulty had revealed she was hoping she had gotten pregnant with a "little Roethlisberger". Antonetti also claimed that she had been asked to travel to Pittsburgh, Pennsylvania in August 2008 in an attempt to "run into" the quarterback. In response, Antonetti advised McNulty she "shouldn't try to chase Mr. Roethlisberger".

On August 8, 2009, the Pittsburgh Post-Gazette published details of an affidavit filed as part of a motion by two of the other defendants named in the suit to relocate the case from Washoe County to Douglas County. In the affidavit, Angela Antonetti, McNulty's former co-worker, delivered a sworn statement that McNulty had bragged to her about having consensual sex with Roethlisberger. As part of the affidavit, Antonetti said she was "absolutely shocked" upon hearing of the case on the radio on July 21. Antonetti explained, "I knew that [her] lawsuit and false allegations would unfairly and unjustly hurt Mr. Roethlisberger".

On April 21, 2010, the NFL's Commissioner Roger Goodell announced that Roethlisberger would be suspended without pay for the first six games of the 2010 season due to a violation of the NFL's personal conduct policy. Roethlisberger was ordered to undergo a league-mandated "professional behavior evaluation" and "must adhere to any counseling or treatment that is recommended by the professional evaluators." The suspension was subsequently reduced to four games.

In December 2011, the suit was ended when the parties agreed to a settlement. Details of the settlement were not made public.

In 2012, Roethlisberger returned to Miami University to complete his college degree, graduating with a Bachelor of Science in Education on May 6, 2012. Roethlisberger walked with the other graduates at the commencement ceremony, with his parents, grandmother, and wife Ashley in attendance. He had planned on finishing his degree sooner, but the Steelers having deep playoff runs earlier in his career prevented him from registering for classes in time for the winter term, only being able to do it after the Steelers were eliminated in the Wild Card round against the Denver Broncos the previous season. Roethlisberger became the second member of the Steelers in less than a year to return to college and complete his degree, with teammate Troy Polamalu doing the same thing the previous offseason during the 2011 NFL lockout.

On December 8, 2013, he passed Terry Bradshaw for most passing touchdowns for a Steelers quarterback.

Roethlisberger was among the celebrities lampooned in the 14th-season premiere of the Comedy Central animated series South Park, appearing in a rehabilitation class for "sex addicts" along with David Letterman, Bill Clinton, and others. Titled "Sexual Healing", the episode aired shortly after the second accusation of sexual assault was made against Roethlisberger.

Roethlisberger sustained another injury against the Oakland Raiders on November 8, 2015, suffering a left mid-foot sprain. Due to this injury, he did not start the following week against the Cleveland Browns, although he was listed as active for the game. However, early in the first quarter, Landry Jones sprained his left ankle, resulting in Roethlisberger entering the game in relief for only the second time in his career. Roethlisberger threw for 379 yards and 3 touchdowns on the way to a Steelers win and an AFC Offensive Player of the Week award; his 379 passing yards were the most by a quarterback in relief since Don Strock threw for 403 yards in the Epic in Miami. On November 29, Roethlisberger threw for 456 yards against the Seattle Seahawks, but he also threw 2 interceptions, and the Seahawks took a 39-30 win.

Roethlisberger was named to his third consecutive and fifth career Pro Bowl on December 20, 2016, and was ranked 22nd on the NFL Top 100 Players of 2017, just one spot below his ranking from the previous year.

The Steelers finished the 2017 season with a 13–3 record, clinching the AFC North division. In the AFC Divisional Round, the Steelers faced the Jaguars. Although the Jaguars had the #1 passing defense in 2017, Roethlisberger finished with 469 passing yards, 5 touchdowns, and an interception, but the Steelers lost 42–45.