A Heffley family road trip to attend Meemaw's 90th birthday party goes hilariously off course thanks to Greg's newest scheme to get to a video gaming convention.

After a comet releases a mysterious virus that begins to kill all of the women in the world, a young couple's relationship is severely tested. They hide out (from both the illness and the savages who hunt the remaining women) in their over-sterilized apartment. Ultimately the duo escapes their self-imposed quarantine to head to the wilderness.