This systematic review and meta-analysis aimed to investigate the effectiveness of exercise interventions in regulating inflammatory biomarkers among individuals with musculoskeletal pain. A comprehensive search of MEDLINE, CINAHL, Web of Science, Cochrane Library, and Google Scholar was conducted from inception to November 2024. Only randomized controlled trials (RCTs) published in English that examined the effects of exercise on inflammatory markers-such as C-reactive protein (CRP), interleukins (ILs), and tumor necrosis factor-alpha (TNF-alpha)-were included. Twenty-three RCTs involving 1128 participants met the inclusion criteria. Meta-analysis of four studies indicated that isokinetic exercise significantly reduced CRP (MD = -0.40, 95% CI: -0.44 to -0.36, p < 0.01, I-2 = 0%), IL-6 (MD = -1.59, 95% CI: -2.61 to -0.56, p < 0.01, I-2 = 97%), and TNF-alpha (MD = -4.24, 95% CI: -5.13 to -3.36, p < 0.01, I-2 = 90%) levels compared to general exercise. These findings suggest that exercise, particularly isokinetic exercise, may reduce systemic inflammation in patients with musculoskeletal pain and provide therapeutic effects beyond mechanical improvement. The review followed PRISMA guidelines and was registered on PROSPERO (CRD42024500081).