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Explanation
The Joke
The comic offers a "pro tip" for thermodynamics tests: whenever a question asks you to determine an object's temperature, simply write "T = 2.73 K" with the caveat "(assume well-mixed Cosmos)." The answer is shown written on what appears to be a test paper.
The joke is that 2.73 Kelvin (more precisely 2.725 K) is the temperature of the Cosmic Microwave Background (CMB) -- the nearly uniform radiation left over from the Big Bang that fills all of space. If you were to take all the matter and energy in the observable universe and mix it evenly, everything would settle to approximately this temperature. So technically, if you "assume a well-mixed Cosmos," this really is the answer to every temperature question.
The Humor
The humor lies in the technically-correct-but-utterly-useless nature of the answer. It is a classic example of a physicist's love of simplifying assumptions taken to an absurd extreme. Physics problems often begin with simplifying assumptions like "assume a frictionless surface" or "assume a spherical cow." Here, Weinersmith takes this to its logical extreme: if you assume the entire universe is well-mixed (i.e., in thermal equilibrium), then every object has the same temperature -- the background temperature of the cosmos. The joke is that while this answer is technically defensible, no professor would ever accept it, and it hilariously dodges the entire point of thermodynamics problems.
References
The Cosmic Microwave Background (CMB) temperature of approximately 2.725 K was first measured by Arno Penzias and Robert Wilson in 1965, earning them the 1978 Nobel Prize in Physics. It represents the cooled remnant of the thermal radiation from the early universe, about 380,000 years after the Big Bang. The "assume a spherical cow" joke is a well-known reference to physicists' tendency to make drastic simplifying assumptions.