Lofton was born in Kingfisher, Oklahoma. He attended Kingfisher High School, where he was a standout player for the Kingfisher Yellowjackets high school football team. A three-year letterman and starter, he also played fullback. He led his team in tackles with 168 during his senior year and 505 over his career, helping lead his team to the 3A state championship in 2003 and helping them advance to the semifinals in 2004. Curtis was coached during high school, including his junior year where he led Kingfisher to its first state championship, by Rick Vancleave, Stan Blundell, Mark Redwine, Larry Hart, and Doug Jech. He rushed for 12 touchdowns as a senior. Lofton was a Parade first team All-American (2004), The Oklahoman All-State (2004), first-team coaches All-state 2004 and also nominated for the March of Dimes Oklahoma Headliners Banquet as one of the top scholar-athletes in the state of Oklahoma.

Lofton totaled five tackles and one tackle for loss in the 2006 Big 12 Championship Game against Nebraska . He closed out the year with four solo tackles and a 14-yard kickoff return against Boise State in the 2007 Fiesta Bowl he also recovered a fumble and was ranked second on the team in special teams tackles with 10. He finished the season with 14 games played and recorded 37 tackles (20 solo), 4.5 tackles for loss, one fumble recovery and one forced fumble.

Was named Big 12 Defensive Player of the Week by his performance against Utah State after recording 12 tackles and one interception which was returned 45 yards for a touchdown and also credited for 16 tackles and one pass defensed at Colorado . In the 2007 Big 12 Championship Game, Lofton picked off a Chase Daniel pass and returned it 26 yards to the Tiger 7-yard line. The Sooner offense cashed in the takeaway with a touchdown to expand OU lead to 28-14. The play tipped the momentum and Oklahoma cruised in with a 38-17 triumph.

Lofton announced on January 14, 2008 that he would forgo his senior season and enter the 2008 NFL Draft.

The Atlanta Falcons selected Lofton in the second round (37th overall) of the 2008 NFL Draft. Lofton was the third linebacker drafted in 2008.

Lofton signed with the New Orleans Saints on March 24, 2012 with a 5-year deal, worth up to $27.5 million. Lofton led the Saints in tackles in the 2012 season (123) and also recorded one sack, two forced fumbles, and two fumble recoveries. He was expected to start at one of the ILB spots in the Saints 3-4 defense in the 2013 season. Lofton was released by the Saints on March 9, 2015.

Lofton signed with the Oakland Raiders on March 11, 2015.

On September 12, 2017, Curtis Lofton officially announced his retirement from the NFL on hobhsports.com. The article, “Just a Kid from Kingfisher: The Story of Curtis Lofton,” was written by his lifelong friend, Adam Arms.