Cushing started all of his 2006 sophomore season as a stand-up defensive end in USC's hybrid 3-4 "Elephant" defense. He finished the season with 57 tackles, including a team-high 13.5 for loss. He also had 4.5 sacks, a blocked punt and a 42-yard kickoff return for a touchdown against Notre Dame. He had seven total tackles, 4.0 tackles for loss and 2.5 sacks in USC's Rose Bowl win against Michigan, earning Defensive MVP honors.
Cushing sat out most of spring practice in 2007 due to a strained hamstring and had knee surgery at the end of the spring. He returned to his natural strong-side linebacker position for the fall season, and suffered a sprained ankle in the season opener against Idaho. Brian Cushing tried to play through the injury in the next two games, but aggravated it against Washington State and missed three games. He returned to the starting lineup for USC's final seven games, finishing the season with 25 total tackles, 2.5 tackles for loss and 1.0 sacks.
Cushing returned to USC for his final season, recording a career-high 73 tackles while playing every game for just the second time in his career. Brian Cushing had a career-high 10 total tackles in USC's win over Ohio State and he recorded his first career interception in USC's win over Stanford. Brian Cushing was a consensus first team All-Pac-10 selection and was a first team All-America selection by Sports Illustrated. He was a second team All-America selection by the Associated Press and The Sporting News. After the 2008 season, Cushing was invited to participate in the 2009 Senior Bowl, where he recorded one solo tackle in a winning effort for the South team.
Cushing missed the entire 2009 preseason with a knee injury, but still earned a starting job and was in the starting lineup Week 1 for the Texans. In November, Cushing earned defensive rookie of the month honors, racking up 43 tackles, a sack and two interceptions. Cushing was one of two AFC rookies (along with Billls safety Jairus Byrd) selected to the Pro Bowl. He finished his rookie season with 134 total tackles, 5.0 sacks and four interceptions, earning AP Defensive Rookie of the Year honors.
In May of 2010, it was revealed that Cushing had failed a drug test and would be suspended for the first four games of the 2010 season for violations of the NFL's performance-enhancing drug policy. Because of the failed test, the AP chose to re-vote for Defensive Rookie of the Year, though Cushing retained the award in the re-vote.