The story's events are set almost entirely in Burden Valley, a small and remote valley somewhere in the USA. It was named after the protagonist's ancestors, who were its first settlers and built a farm in the northern end. The only other inhabitants were the Kleins, a couple who lived over the store and mainly did business with Amish farmers to the south.
The valley is approximately 4 miles long, from Burden Hill in the north to an S-shaped pass in the south called "the gap." The largest of its two streams, Burden Creek, is radioactive because its source is outside the valley. It runs parallel to the road from north to south and exits the valley through the gap. A smaller stream originates from a deep spring on an eastern hillside and feeds a small lake with fish that provide a food source for Ann. The stream then meanders south and joins Burden Creek. Much of the valley is made up of woodlands.
Ann initially thinks the animals in the Valley are probably the last of their species; however, at the end of the book Loomis reveals he has seen birds flying in the distance west of the valley, which opens the possibility of other life as well. There are rabbits and squirrels in the valley. There are also a few crows, which Ann believes survived because only they had the "sense" to stay in the valley, while other birds migrated. There are two cows, a bull calf, and chickens on Ann's farm. Finally, there is the dog, Faro, who belonged to Ann's cousin David.
The most important feature of the valley is that it is somehow separated from the surrounding atmosphere and has its own weather system. Loomis calls it a meteorological enclave created by an inversion (i.e., air only rising, not falling), but he views its existence as so unlikely that it is only a theoretical possibility. Loomis' scientific assessment seems correct because the air in a valley could not be separate from the planet's atmosphere unless the valley's walls were unbroken and rose as high as the tropopause, the level at which temperature begins to increase and air only rises. In any other situation, a valley's air would necessarily mix with surrounding air, and pollution would enter from above. However, for the purposes of this story, readers must suspend disbelief to accept that at least one valley with a self-contained weather system exists, allowing some life to continue after global nuclear war.