The 22-year-old will have an operation in two weeks, which is expected to sideline him for nine months.
Brentford have not disclosed the full details of the injury, which was sustained during their victory against QPR on Friday.
Macleod was stretchered off in the 87th minute of Brentford's 2-0 win at Loftus Road, having come on as a substitute.
The former Scotland Under-21 international was previously ruled out for a year because of various injuries after he joined the Championship club from Rangers in January 2015.

The authorities silence dissent by intimidating journalists and by using "exhaustive" litigation, says the US-based Committee to Protect Journalists. Self-censorship is commonplace.
Television is the most popular medium. The State Committee for TV and Radio operates four national networks and regional channels.
There are more than a dozen private TV stations. Russian TV is widely-watched. Radio can be the sole source of information for those living in very remote areas.
The newspaper sector comprises government-owned and private titles. Most of these publish weekly and circulation figures are low.
There are nearly 1.4 million internet users (InternetLiveStats.com, 2014).
The authorities routinely block websites and social media platforms, including Russia's Odnoklassniki, Facebook and YouTube. But users are adept at using proxies to get around this. Opposition websites operate mainly from abroad.
ImruzNews - private, publishes Monday-Friday
Asia-Plus - private, twice-weekly, in Russian
Jumhuriyat - government-owned, publishes in Tajik three times a week
Khalq Ovozi - government-owned, publishes in Uzbek three times a week
Narodnaya Gazeta - government-owned, publishes in Russian three times a week
Tojikiston - private, Tajik-language weekly
Najot - weekly, published by main opposition Islamic Rebirth Party
Tajik TV- state-run; operates Tajik TV first channel, Safina youth channel, news channel Jahonnamo, children's network Bahoriston and regional channels
Soghd TV - state-run regional station in north
Khatlon TV - state-run regional station in south
SMT (Independent Television of Tajikistan) - private, Dushanbe
Tajik Radio - state-run, operates Radio Tajikistan, Radio Sado-i Dushanbe (Voice of Dushanbe), culture network Radio Farhang, external service Ovoz-i Tojik
Radio Imruz - private, available in all regions
Radio Vatan - Dushanbe, private
Radio Tiroz- Khujand, private
Radio Asia-Plus - Dushanbe, private
Asia-Plus - private, English-language pages
Khovar - state-run, English-language pages
Avesta - private, English-language pages
Brentford midfielder Lewis Macleod will require reconstructive knee surgery and has been ruled out for the season.
[NEXT_CONCEPT]
The media have greater freedoms than in some other Central Asian states, but officials dictate editorial policy at the state media and obstruct critical outlets.