Hamlin entered the 2010 season with great expectations. Many believed he would be a favorite to unseat Jimmie Johnson as Sprint Cup Champion. On January 22, 2010, Hamlin tore the anterior cruciate ligament in his left knee while playing basketball. The decision was made to postpone his surgery until after the season. Hamlin announced on March 27, 2010, to have surgery on his left knee the following Monday. The decision was made to prevent further damage to his knee.
On March 29, 2010, Hamlin won the rain-postponed race at Martinsville Speedway in wild fashion. He beat his Joe Gibbs Racing teammate, Joey Logano, and Jeff Gordon to the finish line. Two days later, Hamlin had knee surgery to repair the torn ligament in his left knee.
On April 19, 2010, three weeks after his surgery, Hamlin worked his way from a 28th starting spot to restart 2nd with 13 laps to go at Texas Motor Speedway. Hamlin was later able to pass Jeff Burton on the outside and hold off Jimmie Johnson to get his 10th career win and his second win in three races.
Less than three weeks later on May 8, Hamlin visited victory lane for the third time in 2010 at Darlington Raceway. He swept the weekend by winning both the Sprint Cup and Nationwide series events. He became the first driver to do so at Darlington since Mark Martin in 1993. He won the Nationwide Series Royal Purple 200 presented by O'Reilly Auto Parts driving the No. 20 for Joe Gibbs Racing on Friday night. He started on the pole and led the most laps to win the race.
Later in the 2010 season, Hamlin finished 43rd in the Emory Healthcare 500 at Atlanta Motor Speedway. This dropped him five spots in the Chase standings, placing him in 10th overall. Despite the drop in the standings, the top 10 drivers in the Chase were locked in after Atlanta, guaranteeing Hamlin a spot in the 2010 Chase for the Sprint Cup. A driver error in the first Chase race on part of Carl Edwards caused Hamlin to spin with 85 to go. With cars ahead running out of fuel, Hamlin barely lost to Clint Bowyer.
After his 3rd-place finish at Kansas, he would climb to 11th in points – 1 point out of the coveted 10th as the series goes to his favorite track, Pocono, where he would have tied himself for the most all-time wins at the track, if he had placed first. After a disappointing 19th-place finish, he moved on to Michigan, a track at which he posted a 1st and 2nd-place finish in 2010. Before the first practice at Michigan, oil pans unapproved by NASCAR were confiscated from the three JGR teams, including Hamlin.