The subject matter of the comic varies, including statements on life and love (some love strips are simply art with poetry), and mathematical or scientific in-jokes. Some strips feature simple humor or pop-culture references. Although it has a cast of stick figures, the comic occasionally features landscapes, intricate mathematical patterns such as fractals (for example, strip #17 "What If" shows an Apollonian gasket), or imitations of the style of other cartoonists (as during "Parody Week").

The comic is available under the Creative Commons Attribution-NonCommercial 2.5 License. New comics are added three times a week, on Mondays, Wednesdays, and Fridays at midnight North American Eastern Time, although on five occasions so far they have been updated every weekday: Parody Week, the "Choices" series, the "1337" series, the "Secretary" series, and the "The Race" series.

The comic began in September 2005 when Munroe decided to scan doodles from his school notebooks and put them on his webpage. Eventually the comic was changed into a stand-alone website, where Munroe started selling T-shirts based on the comic. He currently "works on the comic full time," making xkcd a self-sufficient webcomic. According to Munroe, the comic's name has no particular significance and is simply a four-letter word without a phonetic pronunciation, something he describes as "a treasured and carefully guarded point in the space of four-character strings." The name of the comic is spelled in all lowercase letters, or all capitals.

In May 2007, the comic caught the attention of many by depicting online communities in geographic form. Various websites were drawn as continents, each sized according to their relative popularity and located according to their general subject matter. This put xkcd at number two on The Post-Standard's "The new hotness" list.

xkcd is not an acronym, and Munroe attaches no meaning to the name, except in a joking manner within the comic. He claims that the name was originally a screen name, which he selected as a combination of letters that would be meaningless, as well as phonetically unpronounceable. Some people have, however, inferred other potential meanings for the term xkcd: the Short Minds webcomic, for example, makes much of the fact that the ordinal values of the letters X, K, C and D add up to 42, Douglas Adams' celebrated Answer to Life, the Universe, and Everything.

On September 23, 2007, hundreds of people gathered at 42°23′44″N 71°07′50″W / 42.39561°N 71.13051°W / 42.39561; -71.13051, a park in North Cambridge, Massachusetts whose coordinates were mentioned in a strip, #240. The strip's author appeared, commenting, "Maybe wanting something does make it real," reversing the conclusion he drew in the last frame of the same strip.

In October 2008, The New Yorker magazine online published an interview and "Cartoon Off" between Randall Munroe and Farley Katz. For the "Cartoon-Off," Katz and Munroe each drew: "the Internet, as envisioned by the elderly," "String Theory," "1999," and "your favorite animal eating your favorite food."

While there is no specific storyline to the comic, there are some recurring themes and characters, many of which are touched on in an xkcd parody of the Discovery Channel's I Love the World commercial.

A large number of the strips are mathematics or computer science jokes. These jokes often feature university-level subjects, although many are written in such a way that a clear understanding of the subject is not required to get the punch line. Romance is another subject often visited in the comic, with many strips not intended to be humorous; Munroe is a self-declared fan of Kurt Halsey's bleak romances.

There are also many strips opening with "My Hobby:" and usually depicting the nondescript narrator character describing some type of humorous or quirky behavior often involving language games.