Stroke results in low physical activity, high sedentary behavior (SB), and elevated C-reactive protein (CRP), which are associated with stroke recurrence. This study examined the association between physical activity, SB, and CRP in stroke. CRP data from 185 stroke survivors (M age = 65 years) from the National Health and Nutritional Examination Survey 2009–2010 were analyzed using weighted regression analysis. There was an interaction between physical activity and SB on CRP (estimated-β = −0.079, 95% confidence interval [−0.14, −0.02], p = .011). SB was associated with CRP among those who did not engage in physical activity (estimated-β = 0.068, 95% confidence interval [0.02, 0.11], p = .005), but not among those who did (estimated-β = 0.0003, 95% confidence interval [−0.03, 0.03], p = .988). Physical activity and SB are important modifiable risk factors to lower the risk of recurrent stroke. These findings provide insight into the inflammatory consequences of SB after stroke, particularly among those who also do not engage in physical activity.