OBJECTIVE: Managing Crohn's disease (CD) requires addressing factors beyond medical treatment alone, including health-related quality of life (HRQoL) and physical activity. This study aimed to understand the relationships between different intensities of physical activity, HRQoL, and inflammatory biomarkers in CD, considering sex as a factor that could influence these associations. PATIENTS AND METHODS: A cross-sectional, observational study was conducted in 63 CD patients. Sociodemographic and clinical data, including C-reactive protein and fecal calprotectin determinations, were collected. The Inflammatory Bowel Disease Questionnaire (IBDQ-9) and the Global Physical Activity Questionnaire (GPAQ) were used to measure HRQoL and physical activity, respectively. RESULTS: Although females had similar inflammation levels to males, they engaged in less physical activity and reported lower HRQoL (especially in psychosocial wellbeing). Sedentary behavior and intense physical activity negatively impacted HRQoL in the overall sample and only in females. Higher fecal calprotectin concentrations were associated with poorer HRQoL in the total group and only in males. No correlation was found between inflammation and physical activity. CONCLUSIONS: Sex differences influence the relationship between inflammation, physical activity, and HRQoL in CD. Given the greater impact of CD on emotional and social wellbeing in females, irrespective of physiological measures of inflammation, our findings support considering sex differences, which may inform more individualized approaches to improve HRQoL.