DUFF stands for "Designated Ugly Fat Friend" . It refers to a person in a social group who is perceived as less attractive or popular, serving as a "gatekeeper" for others to get to their more "desirable" friends.
Outside of the movie, the word "duff" has several older and regional uses: THE DUFF – The Review - We Are Movie Geeks The Duff
The story follows high school senior Bianca Piper , who is devastated to learn she has been labeled the DUFF of her friend group. She enlists her neighbor, a charismatic jock named Wesley, to help her reinvent herself and regain her confidence. DUFF stands for "Designated Ugly Fat Friend"