The 25-year-old linebacker, who is also one of the defensive leaders for the 5-0 Texans, was injured in the second quarter of Houston's 23-17 win over the New York Jets on Monday.
"(It's) a big blow to our team," Texans head coach Gary Kubiak said on the team's website. "You feel bad for Brian because he works so hard and is playing so well."
Cushing is expected to undergo surgery in two-to-three weeks once swelling on the injured knee goes down.
The Texans' most valuable player in 2011, Cushing leads the NFL's third-ranked defence this season with 29 tackles and had five on Monday before exiting under his own power after a block by Jets guard Matt Slauson.
Taken in the first round of the 2009 NFL Draft, Cushing had 133 tackles as a rookie, earning him a trip to the Pro Bowl and defensive rookie of the year honours. He also led the team in tackles in 2011.
"You don't replace players like (Cushing)," said Kubiak. "The rest of your football team has got to pick it up and play better. We're going to be calling on everybody else to do their job a little bit better.
Meanwhile suspensions for two players connected to the New Orleans Saints' bounty scandal were reduced by the National Football League (NFL) on Tuesday while two others, including Jonathan Vilma's season-long ban, were upheld.
Linebacker Scott Fujita's three-game ban was dropped to one game and free agent defensive end Anthony Hargrove's eight-game suspension was cut to seven games, the NFL said in a statement.
But Saints linebacker Vilma remained suspended for the entire 2012 NFL season while team mate Will Smith did not get his four-game ban reduced.
The four were punished in May when the NFL identified them as having leadership roles in a programme where players were given cash rewards for knocking opponents out of games from 2009-2011.
But the bans were overturned by an arbitration panel ahead of the season-opening weekend last month in a decision that allowed NFL Commissioner Roger Goodell to put the suspensions back in place if he could prove there was an intent to injure.