To evaluate the variations in COVID-19 case fatality rates (CFRs) across different regions and waves, and the impact of public health interventions, social and economic characteristics, and demographic factors on COVID-19 CFRs, we collected data from 30 countries with the highest incidence rate in three waves. We summarized the CFRs of different countries and continents in each wave through meta-analysis. Spearman’s correlation and multiple linear regression were employed to estimate the correlation between influencing factors and reduction rates of CFRs. Significant differences in CFRs were observed among different regions during the three waves (P < 0.001). An association was found between the changes in fully vaccinated rates (rs = 0.41), population density (rs = 0.43), the proportion of individuals over 65 years old (rs = 0.43), and the reduction rates of case fatality rate. Compared to Wave 1, the reduction rates in Wave 2 were associated with population density (β = 0.19, 95%CI: 0.05–0.33) and smoking rates (β = −4.66, 95%CI: −8.98 – −0.33), while in Wave 3 it was associated with booster vaccine rates (β = 0.60, 95%CI: 0.11–1.09) and hospital beds per thousand people (β = 4.15, 95%CI: 1.41–6.89). These findings suggest that the COVID-19 CFRs varied across different countries and waves, and promoting booster vaccinations, increasing hospital bed capacity, and implementing tobacco control measures can help reduce CFRs.