Globally, the spread and severity of COVID-19 have been distinctly non-uniform. Seasonality was suggested as a contributor to regional variability, but the relationship between weather and COVID-19 remains unclear and the focus of attention has been on outdoor conditions. Because humans spend most of their time indoors and because most transmission occurs indoors, we here, instead, investigate the hypothesis that indoor climate—particularly indoor relative humidity (RH)—may be the more relevant modulator of outbreaks. To study this association, we combined population-based COVID-19 statistics and meteorological measurements from 121 countries. We rigorously processed epidemiological data to reduce bias, then developed and experimentally validated a computational workflow to estimate indoor conditions based on outdoor weather data and standard indoor comfort conditions. Our comprehensive analysis shows robust and systematic relationships between regional outbreaks and indoor RH. In particular, we found intermediate RH (40–60%) to be robustly associated with better COVID-19 outbreak outcomes (versus RH < 40% or >60%). Together, these results suggest that indoor conditions, particularly indoor RH, modulate the spread and severity of COVID-19 outbreaks.