They are widespread throughout North America, ranging from northern Mexico to most of Canada. In Canada, they are found in every province except Newfoundland and Labrador and parts of the far north. In Nova Scotia, they are common across the mainland and parts of Cape Breton, especially in open woodlands, fields, wetlands, and suburban areas. They often den under buildings, decks, rock piles, or in hollow logs. They prefer habitats with a mix of cover and open areas, often near human settlements, where food is abundant.

They are opportunistic omnivores, feeding on whatever is seasonally available. Their diet includes insects, grubs, earthworms, small mammals, bird eggs, amphibians, fruits, seeds, and carrion. They are especially fond of beetles, grasshoppers, and wasp larvae, making them beneficial to farmers and gardeners. In human areas, they may raid compost bins or garbage and consume pet food left outdoors. In fall, they increase food intake to build fat reserves for winter dormancy.

Mating takes place in late February to early April, with delayed implantation possible in some individuals. After a gestation period of about 60–75 days, females give birth to 4–10 kits with an average of 5–7 kits in May or June, usually in a protected den. Kits are born blind and hairless, but develop rapidly, opening their eyes by 3 weeks and leaving the den by 6–7 weeks. Females raise the kits alone and may move them to several dens during the summer. By late summer or early fall, the young disperse. They reach sexual maturity at 10–12 months. In the wild, Striped Skunks live 7 years on average, with high mortality from vehicles and predators; however, in captivity they may live up to 10 years.

Their most famous adaptation is their anal scent glands, which can eject a noxious, oily musk used for defense. The musk causes intense irritation to the eyes and nose and is difficult to remove. They have excellent night vision and hearing, making them effective nocturnal foragers. Their strong forelimbs and claws are adapted for digging up insects and burrowing. Their warning colouration protects them by deterring most predators, although some birds of prey, like Great Horned Owls, are immune to the scent. Striped Skunks also undergo an inactive state of torpor in winter rather than full hibernation. During this time, they stay in their dens, sometimes communally with other skunks to conserve heat, and rely on fat reserves built in the fall.