Isoprene, produced by plants in response to multiple drivers, affects climate and air quality when released into the atmosphere. In turn, climate change may influence isoprene emissions through variations in occurrence and intensity of types of stress that affect plant functions. We test the effects of multiple drivers (temperature, precipitation, soil moisture, drought index, biomass, aerosols, burned fraction) on space retrievals of formaldehyde (HCHO) column concentrations, as a proxy for isoprene emissions, at global and regional scales over the period 2005–2016. We find declines in HCHO column concentrations over the study period across Europe, the Amazon Basin, southern Africa, and southern Australia, and increases across India, China, and mainland Southeast Asia. Temporal effects and the interactions among drivers are analyzed using generalized linear mixed-effects models to explain trends in HCHO column concentrations. Results show that HCHO column concentrations increase with temperature at the global scale and across the Amazon Basin and India–China regions, even under low levels of precipitation, provided that sufficient soil moisture can maintain vegetation functions and the associated isoprene emissions. Water availability sustains isoprene emissions in dry regions such as Australia, where HCHO column concentrations are positively associated with mean precipitation, with this relation intensifying at low levels of soil moisture. In contrast, isoprene emissions increase under water stress across the Amazon Basin and Europe, where HCHO column concentrations are negatively associated with levels of soil moisture and drought as calculated by the Standardized Precipitation–Evapotranspiration Index (SPEI). This study confirms the key role of temperature in modulating global and regional isoprene emissions and highlights contrasting regional effects of water stress on these emissions.