I think the end usability of such a system is low. A computer would handle it fine, but it seems more complex and counterintuitive than it should be to implement at the table. Resistance, from an intuitability standpoint, should protect the target from minor attacks, not major ones. A mechanic like this is always going to be fighting that in the players' brains.
I mean, this would be a special case for like... spellcasters or something.
Like a magical kinetic field that reacts to the force acting against it in equal mesure. It lets bad guys pick up objects, or BREATH, but stops arrows and energy blasts. The faster and more agressive your attack, the more the field protects... So if you knick them with a poisoned blade you might fell them easily, or throw a vial of poisonous gas at their feet when they can't run away, or, at great risk, you could approach and grapple them and trap them in a painful submission lock, or maybe you can startle them with a psionic attack, disabling the shield and now your allies can go to town.
That's certainly a novel solution. I actually kind of like it from a cinematic perspective: many movies or stories have opponents that can be whittled down by a death of a thousand cuts, but who can't be taken out with a single mighty blow.
So yeah, I'd be pretty cool with that.
I think there's room in the game for all sorts of ways for monsters to mitigate damage, and all sorts of ways for player to negate that damage reduction. The more elaborate ones should be limited to set piece encounters, obviously.
Here's another one: creature that take double damage when prone because their soft underbelly is exposed! That would mean the burly Barbarian could flip the creature on its side and make it a cakewalk but it's something you'd need some kind of skill check to know.
Similarly, maybe certain monsters have a built in called-shot mechanic where you can take disadvantage on a (preferably only melee) attack in hopes of stricking a specific part and inflicting more damage than normal?
