Sedentary behavior (SB) is one of the prevalent unhealthy behaviors among breast cancer (BC) patients during chemotherapy and is associated with a variety of adverse health outcomes. Employing a comprehensive theoretical framework to identify the key determinants of SB is a critical step in developing targeted, evidence-based interventions. The purpose of this study was to explore the determinants of SB by using the Capability, Opportunity, Motivation - Behavior model. A cross-sectional survey was conducted and 234 BC patients during chemotherapy were conveniently recruited from a tertiary hospital. The participants completed measures of SB, shoulder function, common cancer-related symptoms, fatigue, exercise self-efficacy, depression, social support, neighborhood built environment, and sociodemographic and clinical characteristics. Descriptive statistics, univariate analysis, Pearson correlation analysis, and multiple linear regression were applied for data analysis. Multiple linear regression results showed that exercise self-efficacy, depression, fatigue, shoulder function, instrumental support, informational support, age, residence status, work status, body mass index, and cancer stage were the main influencing determinants of SB and explained 33.46% of the variance. Findings support the Capability, Opportunity, Motivation - Behavior model's explanatory potential in the context of BC patients' SB and also provide reasonable targets for a behavioral intervention for reducing SB.