Purpose: Among individuals with diagnosed heart failure (HF), the impact of physical activity on systemic inflammation and risk of hospital admissions remains unclear. Therefore, the purpose of this study was to examine the associations between physical activity and (1) systemic inflammation measured through C-reactive protein (CRP) levels and (2) frequency of hospital admissions in those with HF. Methods: We used data from the National Health and Nutrition Evaluation Survey in this observational cross-sectional study to include 377 community-dwelling adults with HF. Demographic, clinical, and functional variables were extracted from the data and included in the regression models as covariates during analysis. Associations between activity and hospital admissions were examined using Poisson regression. Multivariable logistic regression analysis was used for association between CRP and physical activity. Results: We found a direct linear relationship between CRP levels and hospital admissions, with higher levels of CRP significantly associated with greater number of hospital admissions in HF (incidence rate ratio [IRR] = 1.18, P < .001). Similarly, participating in vigorous activity was significantly associated with decreased expected rate of hospital admissions (IRR = 0.38, P = .013 (C.I. = 0.18–0.80) and with a significant decrease in the CRP levels (B = −0.44, P = .018 (C.I. = −0.80 to −0.83). Conclusion: To the best of our knowledge, this is the first study using population-level data to examine the association between physical activity level, systemic inflammation, and hospitalizations in individuals with HF. The findings of this study demonstrate that irrespective of sex, engagement in physical activity at higher intensity levels is strongly associated with favorable health outcomes in older adults with HF.