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Explanation
The Joke
The comic addresses the universal social anxiety of accidentally saying "you too" when someone says "have a good trip" (or "enjoy your meal," etc.) -- a response that does not make sense because the other person is not going on a trip. The comic offers six increasingly absurd strategies for recovering from this blunder, each reinterpreting the sounds "you too" as something other than what was actually said.
The options range from claiming you were referring to a person named "Mr. Yu" (Option 1), to suggesting you thought the plane was a U-2 spy plane (Option 2), to inventing an owl-like noise called a "youd hoo" (Option 3), to claiming you plan to buy a yew-wood statue of the Anglo-Saxon deity Tiu (Option 4), to referencing a friend named Hugh from the Ute tribe (Option 5). The final option, Option 6, simply owns the original statement but reinterprets "trip" to mean Earth's orbit around the Sun -- arguing that everyone is always on a trip, so "you too" is perfectly valid.
The Humor
The comedy comes from the escalating desperation of the cover stories. Each option requires a more elaborate and less plausible backstory to justify the sounds that came out of the person's mouth. The reader recognizes the familiar mortification of the original social gaffe and can appreciate that every proposed recovery is far more embarrassing than the original mistake.
Option 6 is the best punchline because it abandons the phonetic reinterpretation strategy entirely and instead goes on the offensive, turning the embarrassment back on the other person through aggressive pedantry about planetary motion. The character's indignant posture in the final panel -- pointing accusingly while insisting "it is YOU who should feel mildly embarrassed right now" -- captures the absurd bravado of someone who has decided that the best defense is an incomprehensible offense.
References
The U-2 referenced in Option 2 is the Lockheed U-2, a high-altitude reconnaissance aircraft used by the United States during the Cold War. Tiu (or Tiw) referenced in Option 4 is the Anglo-Saxon god of war and the sky, equivalent to the Norse god Tyr, and the origin of the English word "Tuesday." The Ute referenced in Option 5 are a group of Indigenous peoples of the Great Basin region of the western United States.