Wildfires are becoming more frequent and intense on a global scale, raising concerns about their acute and long-term effects on human health. We conducted a systematic review of the current epidemiological evidence on wildfire health risks and a meta-analysis to investigate the association between wildfire smoke exposure and various health outcomes. We discovered that wildfire smoke increases the risk of premature deaths and respiratory morbidity in the general population. Meta-analysis of cause-specific mortality and morbidity revealed that wildfire smoke had the strongest associations with cardiovascular mortality (RR: 1.018, 95% CI: 1.014−1.021), asthma hospitalization (RR: 1.054, 95% CI: 1.026− 1.082), and asthma emergency department visits (RR: 1.117, 95% CI: 1.035− 1.204) in the general population. Subgroup analyses of age found that adults and elderly adults were more susceptible to the cardiopulmonary effects of wildfire smoke. Next, we systematically addressed the toxicological mechanisms of wildfire smoke, including direct toxicity, oxidative stress, inflammatory reactions, immune dysregulation, genotoxicity and mutations, skin allergies, inflammation, and others. We discuss wildfire smoke risk mitigation strategies including public health interventions, regulatory measures, and personal actions. We conclude by highlighting current research limitations and future directions for wildfire research, such as elucidating the complex interactions of wildfire smoke components on human health, developing personalized risk assessment tools, and improving resilience and adaptation strategies to mitigate the health effects of wildfires in changing climate.