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Background: Public health measures to contain the COVID-19 pandemic have led to disruptions in daily life, such as job loss and changes in activity. The present study examines the relationship between pandemic-related life events and disuse (prolonged sitting coupled with inactivity) among adults. Methods: A cross-sectional study of 4084 adults in Israel (September 2020). The primary independent variables were pandemic-related life events, such as job loss. The primary dependent variable was disuse as measured by the Rapid Assessment Disuse Index (RADI). The RADI was examined continuously and dichotomously as a low RADI score (<26: yes/no). Results: Linear regression indicated that experiencing a major life event during the pandemic was associated with lower RADI scores (−1.04; 95% confidence interval, −1.48 to −0.61). Similarly, logistic regression revealed that those experiencing a major life event had 1.18 (95% confidence interval, 1.03 to 1.34) times greater odds for low RADI scores in comparison to those not experiencing an event. Conclusions: Experiencing pandemic-related major life events was linked to less sitting time and increased activity levels among Israeli adults. Future research should examine underlying mechanisms explaining this relationship to facilitate the design and implementation of targeted interventions.