George transferred after a year at Purdue University because the coach who recruited him, Leon Burtnett, was fired. Burtnett's replacement was Fred Akers, who had been known for his teams that used a run-heavy option type offense that required a more mobile quarterback. He subsequently committed to the University of Miami, but he demurred when coach Jimmy Johnson would not guarantee him a starting job at the passer-rich school. George stayed at Illinois for two years, leaving with a year of eligibility remaining after being assured he would be drafted as one of the first five picks of the NFL draft (he was picked No. 1 overall).
The Colts traded to draft George, making him the first pick in the 1990 draft, and signed him to the richest rookie contract in NFL history at the time. George threw 46 interceptions to 41 touchdowns and lost 35 of his 49 career starts as a Colt; his only winning season with the Colts was 1992, where he played ten games and threw 15 interceptions to seven touchdowns. He taunted hometown fans, argued with coach Ted Marchibroda, held out for 36 days, and tried to get a trade; the Colts traded him to the Atlanta Falcons after the 1993 season.
In 1995, George led the Falcons to their first playoff appearance since 1991. On September 22, 1996, in a game against the Philadelphia Eagles, George got into a heated argument on the sidelines with then-Falcons coach June Jones, all of which was caught on camera for a national television audience. Jones suspended George for the remainder of the 1996 season and Atlanta dealt George to the Oakland Raiders after the season. Years after the incident, Jones actually became an advocate for George, stating that the TV argument was overblown and George was actually a good quarterback, a team player and worthy of being on an NFL roster.
George's record with the Falcons was 16-19; he had the best completion percentage (60.5) of his career with 50 touchdowns and 32 interceptions.
In 1997, George threw for 29 touchdown passes and 9 interceptions, for a 91.2 passer rating, as the team finished 4-12. The next year, the offense had changed to head coach Jon Gruden's West Coast scheme, a controlled-pass approach, that did not suit George's strengths. George was inconsistent at the beginning of the year, and later struggled with a groin pull, telling a local radio audience that he was finished for the year. He also ignored the offensive coordinator's play calls during the 1998 season and ran his own plays through a wristband containing plays. The Raiders ended George's Oakland tenure when they signed free-agent quarterback Rich Gannon.
George next played for the Vikings, where he was backup to Randall Cunningham. Cunningham struggled at the start of the 1999 season and was benched. George took over the starting role, in 10 games as a starter going 8-2 with 23 touchdowns, 8.6 yards per attempt and a 94.2 rating in leading Minnesota to the playoffs. George won his first career playoff game, throwing three touchdown passes to lead the Vikings over the Dallas Cowboys 27-10. The Vikings lost the next week to the eventual Super Bowl champion Rams 49-37. When George took too long to agree to terms with the Vikings in the offseason, they chose not to renew George's contract. George ended up signing with Washington.
George had hopes of returning to Minnesota as starting quarterback but was told by head coach Dennis Green to "shop around". After attempting to speak to other teams about securing a starting quarterback job he was eventually offered a $400,000 contract by Minnesota, with incentives totaling up to $1.4 million for a single year. George signed a $14.8 million, four-year contract with the Washington Redskins as Brad Johnson's backup. Johnson went down in week 9; George replaced him, and went 1-2 in the next three games. Johnson returned, but played poorly against the New York Giants. George replaced him and started two games, both losses, after Norv Turner was fired in favor of interim coach Terry Robiskie. After the season, Johnson departed Washington for Tampa Bay, leaving George as the Redskins' starter going into 2001.
Before the 2001 season, Washington hired Marty Schottenheimer as head coach, and Schottenheimer promised to install a West Coast scheme similar to that of Gruden in Oakland. George clashed with Schottenheimer over the offense, though Schottenheimer promised to work George through any problems he might have with the scheme. Washington released George on the heels of a 37-0 Monday Night loss to the Green Bay Packers. After the game, George had a 34.6 passer rating, ranking last in the NFL, and the Redskins were 0-2, having been outscored by opponents 67-3. George was replaced by Tony Banks.
George seemingly retired after his last game in Washington, but he proceeded to make several sideline appearances in the following years. He signed briefly with the Seattle Seahawks in late 2002 as an emergency quarterback.
In 2004, after two years away from the game, the Chicago Bears became the seventh NFL team to employ George, signing him to a one-year contract in November for a partial season backup role, but he never took the field during a game, and was not retained by the Bears for the 2005 season, and was not signed by any team. The Detroit Lions worked him out during their bye week in the event they needed another quarterback; however, George was not offered a contract.
While George spent time on active NFL rosters through 2006, he had not attempted a pass since the 2001 season with the Washington Redskins. It was speculated that he might have replaced third string quarterback Marques Tuiasosopo due to his friendship with Randy Moss. Moss has previously stated that George was his favorite of all the quarterbacks he's worked with. He has also commented in the past that he and George would take weekend fishing trips together when they both lived in Minnesota.
In November 2008, in an appearance on Sirius NFL Radio, George said, "I find it hard to believe there isn't a place in the game for me. My arm feels like I'm 25," he said. "I'm not asking to be a starter, I just want a spot on a team. I still hold out hope I can play in this league. I'm working out three or four days a week, staying ready. Some people might laugh about it. I've been hearing the excuse, 'You're too old,' but I look at guys now playing near 40, and if you can throw it like I can throw it ... Why wouldn't you take a look at me?" He said of coming back: “I’ve been trying to figure out how to get back in, and it just amazes me that I’m not on somebody’s roster. I’ve been throwing two or three times a week, and every time I go out there to throw, I can’t believe I’m not a backup somewhere. I know it’s a young man’s game, but you can’t tell me I’m not better than some of the quarterbacks that are out there. I look at teams like Minnesota or Chicago, and I want to scream at the people in charge, ‘What are you thinking?’ ”
On August 4, 2010, George announced on KFAN Sports radio in Minnesota that he would have been willing to step in for veteran QB Brett Favre if Favre had decided to retire from the Minnesota Vikings.
For years since George's most recent seasons in the NFL, Jason Whitlock has written several columns expressing his belief that George could still play and was deserving of an NFL try-out. George and Whitlock are longtime friends, having played high school football together.