forgetfulness
Explanation
The Joke
Death (depicted as a hooded skeleton figure) stands at the edge of a dark river and tells a man: "To enter the Land of Shadows, you must cross over the River of Forgetfulness." The man replies, "You've told me that, like, four times now." In the next panels, Death says "I..." and then trails off, as the man is already sailing across the river in a small boat, muttering "God I hate this place."
The joke is a logical paradox: the River of Forgetfulness apparently affects Death too. Death keeps forgetting that he has already given the man this speech, so the man has heard the same introduction multiple times. The fact that Death himself is subject to the forgetfulness of his own river creates an absurd, frustrating loop.
The Humor
The comic takes a well-known mythological concept -- the River Lethe from Greek mythology, which causes the dead to forget their earthly lives -- and extends its logic to its absurd conclusion. If there is a River of Forgetfulness in the underworld, surely everyone who works near it, including Death himself, would also be affected. The man's irritated response ("You've told me that, like, four times now") and his exasperated "God I hate this place" give the afterlife the feel of a badly run DMV office, where you keep getting sent back to the same clerk who has no memory of your previous visits. The hovertext ("Holy crap, am I a talking skeleton?! Weiiiiiird.") suggests Death has forgotten even more fundamental things about his own existence.
References
The comic references the River Lethe from Greek mythology, one of the five rivers of the underworld (Hades). In classical myth, souls of the dead would drink from Lethe to forget their past lives before being reincarnated.