In the series, on July 17, 2002, something (speculated to be a plague) simultaneously kills every mammal possessing a Y chromosome - including embryos, fertilized eggs, and even sperm. The only exceptions appear to be Yorick Brown, a young amateur escape artist, and his Capuchin monkey Ampersand.



Society is plunged into chaos as infrastructures collapse and the surviving women everywhere try to cope with the loss of the men, their survivors' guilt, and the knowledge that humanity is doomed to extinction. Vaughan meticulously crafts the new society that emerges out of this chaos, from the conversion of the phallic Washington Monument into a monument to the dead men, to the genesis of the fanatical ultra-feminist Daughters of the Amazon, who believe that Mother Earth cleansed itself of the "aberration" of the Y chromosome, to male impersonators becoming valued romantically and professionally.

Over the course of their journey, Yorick and his friends discover how society has coped in the aftermath of the plague. However, many of the women they encounter have ulterior motives in regard to Yorick. Though the subject matter of the series is entirely serious, Y: The Last Man is also noted for its humor. Yorick in particular is a source of one-liners, although the other characters have their moments as well.