We can watch for unusual situations and ask questions about them.
----
USB device: hi computer i'm a new usb device, i can provide keystroke input
computer: that's a little weird, I already have a keyboard. hey user, do you really want two keyboards at once?
user: wtf no
computer: cool. sorry, usb device. no keystrokes from you.
----
USB device: hi computer I'm a new usb device, I can do keyboard input and provide mass storage
computer: that's a weird combination there buddy. hey user, does this sound cool?
user: weeeird, hmm, yeah how about mass storage so I can see what's on this thing, but no keyboard input.
computer: a pox upon your possibly-suspicious data, my hot-pluggable friend! but tell me about your filesystem.
USB device: hey here are some keystroke events anyway
computer: I'm not listeniiiiiing plus I just told on you to the user
USB device: curses, foiled again
----
USB device: hi computer I'm a new usb device, I can do keyboard input and provide mass storage
computer: that's a weird combination there buddy. plus i already have a keyboard plugged in. oh wait the user said you were okay and told me to never ask again.
USB device: cool
----
USB device: hi computer I'm a new usb device, I can do @$T%^&#R&ssnhf^23&298>>>
computer: that's a nice buffer overflow you have there, darling. take me, I'm yours!
USB device: p0n'd. here's a payload!
user: huh, that usb key I found in the parking lot of the nuclear plant doesn't work. Oh well. throws it away
payload: all yr base belong to us
----
Obviously "not plugging untrusted hardware into their machine" is still useful. And users often just say 'okay' to everything anyway. But "a weird thing is happening, are you cool with this?" would be a nice line of defense.