The Portuguese midfielder, who joined the club from Sporting CP in January 2020, is widely regarded as United’s best signing in the post-Sir Alex Ferguson era.
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The milestone comes five months after Fernandes turned down a lucrative offer from Saudi Pro League side Al-Hilal.
"I am very proud, it is a privilege, an honour," Fernandes told MUTV ahead of the match.
"This is far, far from everything I have dreamed about, you know. I just wanted to play football when I was a kid and now getting into this club, having the chance to play 300 times for this club, it is something I am very grateful for."
Fernandes has claimed just two trophies with Manchester United; the Carabao Cup in 2023 and the FA Cup in 2024.