Public compliance is paramount for the success of public health measures and decision making, such as lockdowns, in controlling the spread of diseases. The aim of this population-based cross-sectional study was to investigate the level of reported compliance with home isolation among the adult Israeli population ( = 940) during the first three national lockdowns, compliance with a potential fourth national lockdown if enacted, risk perception of COVID-19, vaccination uptake status, perceived effectiveness of the vaccine, and compliance with additional protective health behaviors (e.g., mask wearing and social distancing). Following widespread compliance with initial lockdowns (90.7% reported "high" or "very high" compliance), as few as 60.1% of participants indicated that they would comply with a fourth lockdown if the government decides to enact it. Non-vaccinated individuals reported the lowest levels of compliance with previous lockdowns, compared to participants who received one or two vaccines and participants vaccinated with three doses. Adjusted for gender and age, the results suggest that fearing being infected with COVID-19, perceiving the vaccine to be effective, and reporting being compliant with other health behaviors-such as mask wearing and maintaining social distance from others-are predictors of lockdown compliance. Considering the effect of pandemic lockdown fatigue, there is little support for additional lockdowns among the Israeli public, unless dramatic changes occur in the characteristics of the COVID-19 pandemic. Compliance with lockdowns is reduced among individuals who are at higher risk of contracting COVID-19, therefore rendering this non-pharmaceutical intervention even less effective in reducing the spread of the disease.