BackgroundThe Omicron variant of SARS-CoV-2 is more highly infectious and transmissible than prior variants of concern. It was unclear which factors might have contributed to the alteration of COVID-19 cases and deaths during the Delta and Omicron variant periods. This study aimed to compare the COVID-19 average weekly infection fatality rate (AWIFR), investigate factors associated with COVID-19 AWIFR, and explore the factors linked to the increase in COVID-19 AWIFR between two periods of Delta and Omicron variants.Materials and methodsAn ecological study has been conducted among 110 countries over the first 12 weeks during two periods of Delta and Omicron variant dominance using open publicly available datasets. Our analysis included 102 countries in the Delta period and 107 countries in the Omicron period. Linear mixed-effects models and linear regression models were used to explore factors associated with the variation of AWIFR over Delta and Omicron periods.FindingsDuring the Delta period, the lower AWIFR was witnessed in countries with better government effectiveness index [β = −0.762, 95% CI (−1.238)–(−0.287)] and higher proportion of the people fully vaccinated [β = −0.385, 95% CI (−0.629)–(−0.141)]. In contrast, a higher burden of cardiovascular diseases was positively associated with AWIFR (β = 0.517, 95% CI 0.102–0.932). Over the Omicron period, while years lived with disability (YLD) caused by metabolism disorders (β = 0.843, 95% CI 0.486–1.2), the proportion of the population aged older than 65 years (β = 0.737, 95% CI 0.237–1.238) was positively associated with poorer AWIFR, and the high proportion of the population vaccinated with a booster dose [β = −0.321, 95% CI (−0.624)–(−0.018)] was linked with the better outcome. Over two periods of Delta and Omicron, the increase in government effectiveness index was associated with a decrease in AWIFR [β = −0.438, 95% CI (−0.750)–(−0.126)]; whereas, higher death rates caused by diabetes and kidney (β = 0.472, 95% CI 0.089–0.855) and percentage of population aged older than 65 years (β = 0.407, 95% CI 0.013–0.802) were associated with a significant increase in AWIFR.ConclusionThe COVID-19 infection fatality rates were strongly linked with the coverage of vaccination rate, effectiveness of government, and health burden related to chronic diseases. Therefore, proper policies for the improvement of vaccination coverage and support of vulnerable groups could substantially mitigate the burden of COVID-19.