Multiple COVID-19 waves have been observed worldwide, with varying numbers of positive cases. Population-level immunity can partly explain a transient suppression of epidemic waves, including immunity acquired after vaccination strategies. In this study, we aimed to estimate population-level immunity in 47 Japanese prefectures during the three waves from April 2021 to September 2022. For each wave, characterized by the predominant variants, namely, Delta, Omicron, and BA.5, the estimated rates of population-level immunity in the 10–64-years age group, wherein the most positive cases were observed, were 20%, 35%, and 45%, respectively. The number of infected cases in the BA.5 wave was inversely associated with the vaccination rates for the second and third injections. We employed machine learning to replicate positive cases in three Japanese prefectures to validate the reliability of our model for population-level immunity. Using interpolation based on machine learning, we estimated the impact of behavioral factors and vaccination on the fifth wave of new positive cases that occurred during the Tokyo 2020 Olympic Games. Our computational results highlighted the critical role of population-level immunity, such as vaccination, in infection suppression. These findings underscore the importance of estimating and monitoring population-level immunity to predict the number of infected cases in future waves. Such estimations that combine numerical derivation and machine learning are of utmost significance for effective management of medical resources, including the vaccination strategy.