Populations of many mammal species living in grassland ecosystems across North America have been reduced greatly over the past 200 years due to conversion of native prairie to human-related uses. Foremost among these species is the black-tailed prairie dog (Cynomys ludovicianus), populations of which have declined an estimated 98% during that time. In addition to anthropogenic factors including plague, black-tailed prairie dog populations can vary in size in response to grazing by native ungulates, fire, and precipitation. Colonies in the Northern Great Plains have expanded and contracted during dry and wet periods, respectively. Drought reduces vegetation height; tall vegetation is known to limit colony expansion, possibly due to increased predation risk. We used mixed-effects models to analyze data sets of colony areas of black-tailed prairie dogs spanning 16–22 years and 983 total colony counts, from 142 unique colonies at Badlands National Park and Wind Cave National Park, South Dakota, United States, and Scotts Bluff National Monument, Nebraska, United States, to relate areal dynamics of colonies over time to total annual precipitation, drought stress, and plague. We also analyzed the relationship between active-burrow densities and precipitation and drought stress using 7 years of data from 271 colony counts at Badlands National Park. Black-tailed prairie dog colonies expanded in response to drought conditions in all three national parks, with colonies in Wind Cave National Park exhibiting a time-delayed response. In addition, colony area was negatively related to total accumulated precipitation for the preceding 12 months for Scotts Bluff National Monument. Active-burrow density at Badlands National Park decreased in response to drought stress with a time lag of 24–36 months. Plague first was reported at Badlands National Park in 2008 and colony areas decreased dramatically and rapidly during plague epizootic events. Our results support observations that black-tailed prairie dog colonies in the Northern Great Plains expand and contract in response to drought stress and wet weather. Furthermore, our findings provide new insights into the role of climate on a keystone species of conservation importance and demonstrate the value of collecting long-term ecological data.