The healthcare system is a vital element for any community, as it extremely affects the socio-economic development of any country. The current study aims to assess the performance of the healthcare systems of the countries above fifty million citizens in facing the spread of the COVID-19 pandemic since late December 2019. For this purpose, seven scenarios were adopted via the DEA methodology with six variables, which are the number of medical practitioners (doctors and nurses), hospital beds, Conducted Covid-19 tests, affected cases, recovered cases, and death cases. To shed light on the relative efficiency of drivers, the Tobit analysis was used. Besides, the study carried out various statistical tests for the DEA models' findings to validate the choice of the variables and the obtained scores. The DEA results reveal that less than half of the considered countries are relatively efficient. Moreover, the Tobit regression analysis showed that the main impact on the efficiency scores was due to the number of affected and recovered cases. Finally, the results of the tests of Spearman, Mann-Whitney U, and Kruskal-Wallis H indicate the internal validity and robustness of the chosen DEA models. The current study findings raise important implications, which can be helpful for decision makers regarding continuous improvement of performance, in which the findings assert the importance of achieving the best practices regarding relative efficiency through the linkage between the healthcare systems’ resources, and the needed outputs.