As a senior in the 1995 season, George rushed for a school record 1,927 yards and 24 touchdowns, an average of 148.23 yards per game, while also catching 47 passes for 417 yards and another score (George only caught 16 passes in his first three seasons). One of his best performances of the year was in a 45-26 win over the University of Notre Dame, where he rushed for 207 yards, his third 200-yard game of the season. He also rushed for a school-record 314 yards and scored 3 touchdowns in OSU’s victory over Illinois.

George was the first-round draft selection (14th overall pick) of the Houston Oilers (now the Tennessee Titans) in 1996 NFL Draft, being selected after Jerome Bettis elected to be traded to the rival Pittsburgh Steelers over the Oilers when the St. Louis Rams replaced Bettis with Lawrence Phillips. George won the NFL Rookie of the Year award in 1996, and was the Oilers/Titans’ starting tailback through 2003, never missing a start. He made the Pro Bowl four consecutive years (1997–2000), and assisted the Titans to a championship appearance in Super Bowl XXXIV, where they lost to the St. Louis Rams 23-16. George gained 391 combined rushing and receiving yards in the Titans’ three playoff games that year and went on to rush for 95 yards, catch two passes for 35 yards, and score two touchdowns in the Super Bowl.

Though George rushed for 1,000 yards in all but one season, numerous sports writers suggested that a heavy workload caused a decline in George’s productivity. In five of his eight seasons with the Titans, George carried the ball over 330 times. In 2001, George averaged just 2.98 per carry, the fourth lowest number in league history among running backs with more than 200 rushing attempts in a season. George’s decline in production along with several toe and ankle injuries were contributing factors in Titans owner Bud Adams’ decision to release him on July 21, 2004 in part due to salary cap considerations, after George would not agree to a pay cut.

On July 23, 2004, George signed a one-year contract with the Dallas Cowboys for $1.5 million plus incentives that could have earned him more than the $4.25 million he would have made under his previous contract with the Titans. George only started 8 games for Dallas while rookie Julius Jones was out for two months with a fractured scapula. He became the backup running back when Jones returned midway through the season, finishing with 432 yards on 132 carries and 4 touchdowns. He officially retired in 2006.

In 2004, Eddie George married American singer, rapper, actress, and author Tamara Johnson George. She was best known for being a part of the group Sisters with Voices and being a contestant on the eighteenth season of the CBS reality show Survivor. On the 12th episode, “The Ultimate Sacrifice”, George surprised his wife, by visiting her on Exile Island.

On October 1, 2006, George was appointed spokesperson for Tennessee’s GetFitTN program by Governor Phil Bredesen. The initiative is aimed at preventing Type 2 diabetes and the promotion of healthier, more active lifestyles. On Saturday, April 28, 2007, George ran the Country Music Half Marathon (ending just outside then LP Field, now Nissan Stadium) in an unofficial time of 2:04:08. He wore race number 27 during the race, just as he wore number 27 during his college and NFL careers. George later stated that completing the race was tougher than playing in the NFL. In 2008, George campaigned for Senator Barack Obama’s presidential bid.

George’s jersey was retired by the Titans during a halftime ceremony against the Indianapolis Colts on September 15, 2019, along with former teammate Steve McNair who was killed in 2009.