Advancements in vaccination technologies mitigate disease transmission risks but may inadvertently suppress the behavioral immune system, an evolved disease avoidance mechanism. Applying behavioral immune system theory and utilizing robust big data analytics, we examined associations between rising vaccination coverage and government policies, public mobility, and online information seeking regarding disease precautions. We tested whether cultural tightness–looseness moderates the relationship between mass immunization and disease prevention vigilance. Comprehensive time series analyses were conducted using American data (Study 1) and international data (Study 2), employing transfer function modeling, cross‐correlation function analysis, and meta‐regression analysis. Across both the US and global analyses, as vaccination rates rose over time, government COVID‐19 restrictions significantly relaxed, community mobility increased, and online searches for prevention information declined. The relationship between higher vaccination rates and lower disease prevention vigilance was stronger in culturally looser contexts. Results provide initial evidence that mass immunization may be associated with attenuated sensitivity and enhanced flexibility of disease avoidance psychology and actions. However, cultural tightness–looseness significantly moderates this relationship, with tighter cultures displaying sustained vigilance amidst immunization upticks. These findings offer valuable perspectives to inform nuanced policymaking and public health strategies that balance prudent precautions against undue alarm when expanding vaccine coverage worldwide.