Climate change has brought increasing attention to the assessment of health risks associated with climate and extreme events. Drought is a complex climate phenomenon that has been increasing in frequency and severity both locally and globally due to climate change. However, the health risks of drought are often overlooked, especially in places such as the United States, as the pathways to health impacts are complex and indirect. This study aims to conduct a comprehensive assessment of the effects of monthly drought exposure on respiratory mortality for NOAA climate regions in the United States from 2000 to 2018. A two-stage model was applied to estimate the location-specific and overall effects of respiratory risk associated with two different drought indices over two timescales (the US Drought Monitor and the 6-month and 12-month Evaporative Demand Drought Index). During moderate and severe drought exposure, respiratory mortality risk ratio in the general population increased up to 6.0% (95% Cr: 4.8 to 7.2) in the Northeast, 9.0% (95% Cr: 4.9 to 13.3) in the Northern Rockies and Plains, 5.2% (95% Cr: 3.9 to 6.5) in the Ohio Valley, 3.5% (95% Cr: 1.9 to 5.0) in the Southeast, and 15.9% (95% Cr: 10.8 to 20.4) in the Upper Midwest. Our results showed that age, ethnicity, sex (both male and female), and urbanicity (both metro and non-metro) resulted in more affected population subgroups in certain climate regions. The magnitude and direction of respiratory risk ratio differed across NOAA climate regions. These results demonstrate a need for policymakers and communities to develop more effective strategies to mitigate the effects of drought across regions.