Background: Inflammatory cytokines and acute phase proteins increase with aging, promoting a chronic low-grade inflammation. Studies have shown a positive effect of exercise on inflammatory markers in older persons. Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) are the main biomarkers investigated. However, it is unclear if exercise could decrease all these biomarkers. Purpose: The aim was to analyze the effect of chronic exercise on IL-6, TNF-α, and CRP levels in older persons. Methods: Preferred Reporting Items in Systematic Reviews and Meta-analyses guidelines were adopted. Original articles that investigated the effect of chronic exercise on inflammatory profile of the elderly persons were eligible for this review. The databases PubMed, PEDro, EBSCO, and BioMed Central were searched. Three reviewers evaluated each publication for reducing bias. Data about IL-6, TNF-α, and CRP were collected and analyzed. A standardized mean difference based on estimated pooled effect size was calculated considering heterogeneity index (I²) and random effect. Results: Seventy-six studies were retrieved from databases, and 8 of them were analyzed. IL-6 and CRP levels decreased after chronic exercise (overall effect P < .05). Conclusion: Regular exercise decreases IL-6 and CRP levels in older persons. The effect of exercise on TNF-α remains unclear.