Background <p>Cancer patients experience cardiovascular and metabolic comorbidities that worsen treatment tolerance, and increase mortality risk. Metabolic dysregulation, chronic inflammation, and prolonged sedentary behavior are recognized contributors to these adverse outcomes.</p> Objective <p>This study aimed to examine the associations of metabolic markers, inflammatory biomarkers, and sedentary time with major comorbidities among cancer patients.</p> Methods <p>A cross-sectional study analyzed data from 2021–2023 National Health and Nutrition Examination Survey. A total of 692 adults with a self-reported history of cancer were included. Body mass index (BMI), waist-to-hip ratio (WHR), blood pressure, pulse rate, high-sensitivity C-reactive protein (hs-CRP), neutrophil-to-lymphocyte ratio (NLR), and sedentary time were categorized into tertiles. Multivariate logistic regression models estimated unadjusted and adjusted odds ratios for cardiovascular, respiratory, metabolic comorbidities, controlling for age, sex, race/ ethnicity, education level, smoking status, and physical activity level.</p> Results <p>After adjustment, higher BMI was significantly associated with congestive heart failure, hypertension, and diabetes. Higher WHR was associated with heart attack and diabetes. SBP showed bidirectional associations, with the highest tertile associated with cardiovascular disease, respiratory disease, and diabetes. Hs-CRP was associated with congestive heart failure and hypertension. Longer sedentary time was associated with higher odds of congestive heart failure, hypertension, and diabetes.</p> Conclusions <p>After adjusting for key confounders, metabolic indicators, inflammatory biomarkers, and sedentary time were associated with cardiometabolic comorbidities among cancer patients. BP parameters showed complex bidirectional associations with cardiovascular and metabolic outcomes. These finding highlight the importance of comprehensive and individualized risk assessment in cancer survivorship care.</p>