The Hooded Skunk is most common in the arid lowlands (Davis and Russell 1954), but also occurs in deciduous or ponderosa forest, forest edges, pastures, rocky canyons, and riparian habitats (Baker 1956, Findley et al. 1975, Janzen and Hallwachs 1982). This species seems to benefit from human-disturbed areas and can be abundant around human populations. Typically, M. macroura occurs from sea level to 2,440 m (Hubbard 1972), but it was also found at higher elevations in Mexico (Davis and Russell 1954) and in Arizona (Hoffmeister 1986). In Guerrero, Mexico, the species is widespread but scattered below 1,830 m (Davis and Lukens 1958). In Mexico, Hooded Skunk individuals occupy home ranges of 2.8–5.0 km² (Ceballos and Miranda 1986). It consumes mainly insects, fruits, small vertebrates, and bird eggs (Patton 1974, Reid 2009). In Arizona, U.S.A., where it overlaps with Striped Skunk Mephitis mephitis, competition between the two is minimal (Hass and Dragoo in press). The life history is discussed in Dragoo and Hass in prep.). The various parasites and diseases are discussed in Hass and Dragoo (2006) and Dragoo and Hass in (prep.).

Mephitis macroura occurs from the southern United States (southwestern Texas, southwestern New Mexico, and southeastern Arizona), throughout Mexico, into Guatemala, Honduras, Nicaragua, and northwest Costa Rica. (Hall 1981, Janzen and Hallwachs 1982, Rosatte 1987, Reid 1997, Dragoo 2009). There are no recent records from Texas (Dragoo 2009, J.W. Dragoo pers. comm. 2016).

The species does not have any specific protection status in Central America (de la Rosa and Nocke 2000).