This study investigated whether physical activity (PA) influences the association between depression risk and low-grade inflammation. This was a cross-sectional study including 8,048 adults (18-59y). Depression symptoms were evaluated with the Beck depression inventory (BDI) and physical activity through the international physical activity questionnaire. Adults with infectious and inflammatory diseases were excluded. Blood samples were collected, including high sensitivity C-reactive protein (CRP), a marker of low-grade inflammation when ≥3mg/L. Additional measures of LDL-C, HDL-C, triglycerides and fasting glucose were also determined. Sex, chronological age, tobacco smoking, alcohol drinking, body mass index, dyslipidemia, high blood pressure and fasting glucose were used as covariates. Mediation models were conducted using the procedures of Karlson Holm Breen. Adults with elevated CRP (≥3mg/L) compared to those with low CRP (<3mg/L) presented with higher BDI scores [8.5%(95%CI:7.2%-10.1%) vs. 5.8%(95%CI:5.2-6.4)] as well as higher prevalence of physical inactivity 67.4% (95%CI:64.9-69.9) vs. 59.7% (95%CI:58.4-60.9). The prevalence of elevated CRP was highest in physically inactive adults with greater depression risk. Models revealed that physical activity risk explained 13% of the association between depression risk and elevated CRP (p=0.035), independently of potential confounders. Physical activity may reduce the association between depression symptoms and elevated CRP. Future longitudinal research is required to determine the directionality of the relationships observed.