Extreme heat and wildfire smoke events are increasingly co-occurring in the context of climate change, especially in California. Extreme heat and wildfire smoke may have synergistic effects on population health that vary over space. We leveraged high-resolution satellite and monitoring data to quantify spatially varying compound exposures to extreme heat and wildfire smoke in California (2006–2019) at ZIP Code Tabulation Area (ZCTA) level. We found synergistic effects between extreme heat and wildfire smoke on daily cardiorespiratory hospitalizations at the state level. We also found spatial heterogeneity in such synergistic effects across ZCTAs. Communities with lower education attainment, lower health insurance coverage, lower income, lower proportion of automobile ownership, lower tree canopy coverage, higher population density, and higher proportions of racial/ethnic minorities experienced higher synergistic effects. This study highlights the need to incorporate compound hazards and environmental justice considerations into evidence-based policy development to protect populations from increasingly prevalent compound hazards.