This study examines the influence of body mass index (BMI) and systemic inflammation on the relationship between physical activity and chronic pain conditions. We used data from the National Health and Nutrition Examination Surveys (NHANES, 2003-2004 and 2009-2010 waves), a population-based representative sample of the US population. Chronic pain conditions (neck, low back, hip, joint pain, and migraine) were defined as persistent pain for more than three months using self-reported questionnaires. Vigorous and moderate physical activity and sedentary time were collected using validated instruments. Weighted logistic regression models were used to test the adjusted associations and effect modifications. We included 9809 individuals (mean age of 46.58 and 51% women). We found a protective adjusted association between vigorous physical activity and chronic neck, low back, and hip pain (2003-2004: OR = 0.798, 95% CI, 0.647-0.984; 2009-2010: OR = 0.629, 95% CI, 0.474-0.833). Consistently, higher sedentary time was associated with higher chronic pain prevalence. Likewise, vigorous physical activity was protective for chronic migraine pain (2003-2004: OR = 0.697, 95% CI, 0.517-0.939). However, it was not for chronic joint pain. Moderate physical activity does not have a protective association in our sample. Furthermore, this protective association was attenuated by high BMI levels ( = 0.011) and high CRP ( = 0.006). Vigorous physical activity has a protective association with chronic pain. People with obesity and high systemic inflammation presented an attenuated beneficial association. Our results suggest that pain condition, body composition, and systemic inflammation should be considered for the personalization of community-based physical activity interventions to prevent chronic pain conditions.