Abstract The protective effect of physical activity on breast cancer incidence may partially be mediated by inflammation. Systematic searches of Medline, EMBASE, and SPORTDiscus were performed to identify intervention studies, Mendelian randomization studies, and prospective cohort studies that examined the effects of physical activity on circulating inflammatory biomarkers in adult women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the Grading of Recommendations Assessment, Development, and Evaluation system was used to determine the overall quality of the evidence. Thirty-five intervention studies and one observational study met the criteria for inclusion. Meta-analyses of randomized controlled trials (RCT) indicated that, compared with control groups, exercise interventions reduced levels of C-reactive protein (CRP) [standardized mean difference (SMD) = −0.27, 95% confidence interval (CI) = −0.62 to 0.08), tumor necrosis factor alpha (TNFα, SMD = −0.63, 95% CI = −1.04 to −0.22), interleukin-6 (IL6, SMD = −0.55, 95% CI = −0.97 to −0.13) and leptin (SMD = −0.50, 95% CI = −1.10 to 0.09). Owing to heterogeneity in effect estimates and imprecision, evidence strength was graded as low (CRP, leptin) or moderate (TNFα and IL6). High-quality evidence indicated that exercise did not change adiponectin levels (SMD = 0.01, 95% CI = −0.14 to 0.17). These findings provide support for the biological plausibility of the first part of the physical activity—inflammation—breast cancer pathway.