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Explanation
The Joke
A woman tells her conversation partner that she doesn't mind that they've "started disagreeing" with her political views, but she does object to his characterizing her views as "pathological." He responds with a pseudo-intellectual defense: "By 'pathological disagreement,' I can write off entire regions of mental possibility while simultaneously imagining myself to be considering all views as positively as possible." In the final panel, the woman delivers the verdict: "Best as I can tell, you who actively disagree with me are who you actually are -- you're experiencing your own mental pathology."
The comic skewers a common rhetorical move in political discourse: dismissing the other side's views not just as wrong, but as psychologically defective or "pathological." Instead of engaging with the substance of a disagreement, one simply categorizes the other person's entire worldview as a kind of mental illness, which conveniently allows you to ignore everything they say while still feeling like an open-minded person.
The Humor
The humor lies in the character's oblivious self-contradiction. He explicitly states that calling his opponent's views "pathological" lets him "write off entire regions of mental possibility" while "simultaneously imagining" himself to be open-minded -- and he says this as though it's a perfectly reasonable thing to do. The title text ("If he were more sensible, he'd realize people who disagree with him are actually just possessed by the devil") amplifies the joke by showing that the alternative explanations for disagreement are always just as dismissive, just with different framing. SMBC is highlighting how intellectual laziness can disguise itself as sophistication.