Background: This study examined the effects of environmental, demographic, and lifestyle factors on leisure-time physical inactivity (LTPI). Methods: Analyses were based on county-level data in the contiguous United States. Statistical methods included simple regression, univariate, and multivariate 2-level organizational models (mixed models), and the intraclass correlation coefficient. Results: Higher average daily maximum air temperature was directly and indirectly (through smoking and obesity) positively associated with LTPI. Higher average fine particulate matter was positively associated with LTPI. Higher precipitation was negatively associated with LTPI. Altitude (≥1500 m) was associated with lower LTPI, directly because of better physical health at higher altitude and indirectly through temperature, fine particulate matter, precipitation, poverty, smoking, and obesity. Urban dwelling had direct and indirect (through poverty) negative associations with LTPI. Poverty had direct and indirect (through smoking and obesity) associations with LTPI. Smoking, poverty, and black race were each positively associated with LTPI. The association between black race and LTPI was explained by poverty. Modifying influences of gender, precipitation, and altitude were identified. Conclusions: The significant effects of temperature, fine particulate matter, precipitation, altitude, urban dwelling, poverty, smoking, and obesity on LTPI were both direct and indirect, and sex, precipitation, and altitude modified many of these associations.