The Scot, a 71st minute substitute for Josh McEachran, went down 10 minutes later challenging for the ball. After receiving extensive treatment on the pitch, he was stretchered off receiving oxygen.
The club's medical staff have investigated the issue but Macleod requires reconstructive surgery, which could even rule him out for the start of the 2017/18 season.
Brentford's head of medical, Neil Greig, told the club's official website: “Unfortunately Lewis's injury is a serious one. Clearly we're obliged to keep the full details confidential; however I can say that it is an injury that will need surgery in order for him to recover.
“We have agreed a plan for the coming weeks with our knee consultant and Lewis will undergo surgery in around two weeks’ time, which will provide appropriate time for the injury to calm down and for us to restore normal movement to the joint.
“The recovery from an injury of this nature ordinarily takes around nine months; therefore a return toward the beginning of next season is likely.
“Lewis's outlook has been incredibly positive since learning the full extent of his injury and this attitude will stand him in good stead during his recovery.
“As a staff we're very well aware of Lewis's strength of character, which he's demonstrated since his arrival and which compliments his outstanding talent as a footballer.
“Everyone at the club will of course provide Lewis with our fullest support and a platform for him to return in the best physical condition possible.”
Macleod has had an injury hit time at Griffin Park, arriving with a hamstring injury and then suffering setbacks along the way.
He joins Alan Judge, Callum Elder and Rico Henry on the treatment table.