Background: The COVID-19 pandemic had a profound impact on the global health system and economic structure. Although the implementation of lockdown measures achieved notable success in curbing the spread of the pandemic, it concurrently incurred substantial socioeconomic costs., Objective: The objective of this study was to delineate an equilibrium between the economic losses and health benefits of lockdown measures, with the aim of identifying the optimal boundary conditions for implementing these measures at various pandemic phases., Methods: This study used a model to estimate the half-lives of the observed case fatality rates of different strains. It was based on global infection and death data collected by the World Health Organization and strain sequence time series data provided by Nextstrain. The connection between the health benefits and economic losses brought by lockdown measures was established through the calculation of disability-adjusted life years. Taking China's city lockdowns as an example, this study determined the cost-benefit boundary of various lockdown measures during the evolution of COVID-19., Results: The study reveals a direct proportionality between economic losses due to lockdowns and the observed case fatality rates of virus strains, a relationship that holds true irrespective of population size or per capita economic output. As SARS-CoV-2 strains evolve and population immunity shifts, there has been a notable decrease in the observed case fatality rate over time, exhibiting a half-life of roughly 8 months. This decline in fatality rates may offset the health benefits of maintaining unchanged lockdown measures, given that the resultant economic losses might exceed the health benefits., Conclusions: The initial enforcement of lockdown in Wuhan led to significant health benefits. However, with the decline in the observed case fatality rate of the virus strains, the economic losses increasingly outweighed the health benefits. Consequently, it is essential to consistently refine and enhance lockdown strategies in accordance with the evolving fatality and infection rates of different virus strains, thereby optimizing outcomes in anticipation of future pandemics., (©Wenxiu Chen, Bin Zhang, Chen Wang, Wei An, Shashika Kumudumali Guruge, Ho-kwong Chui, Min Yang. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 07.06.2024.)