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(1) Background: The association of COVID-19 infection and mortality with mobility and weather in Indiana and Kentucky was compared for the period from 1 March to 15 May 2020. (2) Methods: The risk of COVID-19 infection and mortality was evaluated using Cox regressions with the following covariates: mobility (retail/recreation, grocery/pharmacy, and workplace), weather (precipitation, minimum and maximum temperature, ultraviolet [UV] index), and metropolitan status. (3) Results: A higher maximum temperature (adjusted hazard ratioinfection (aHRi) = 1.01; adjusted hazard ratiodeath (aHRd) = 1.001), metropolitan status (aHRi = 1.12; aHRd = 2.05), and a higher minimum temperature (aHRi = 1.01) were associated with increased risks of COVID-19 infection and/or mortality. Protection against COVID-19 infection and/or mortality was associated with retail/recreation (aHRi = 0.97; aHRd = 0.937), grocery/pharmacy (aHRi = 0.991; aHRd = 0.992), workplace (aHRi = 0.99; aHRd = 0.965), precipitation (aHRi = 0.999; aHRd = 0.9978), UV index (aHRi = 0.37; aHRd = 0.748), and a higher minimum temperature (aHRd = 0.994). COVID-19 infection (aHRi = 1.18) and mortality (aHRd = 1.59) risks were higher in Indiana compared to Kentucky. (4) Conclusions: COVID-19 infection and mortality were 18% and 59% more likely among Indiana residents compared to Kentucky residents, respectively. This may be attributed to variations in stay-at-home order compliance and enforcement between Indiana and Kentucky.