Background: Accumulated evidence has proved that both neuroinflammation and neuroprotection existing at the stage of mild cognitive impairment (MCI) may mediate its progression, which can conversely be modulated by physical activity (PA). However, further research is needed to clarify which factors are involved in that process. Objectives: To identify the impact of PA on inflammatory cytokines and neuroprotective factors in individuals with MCI. Methods: Four databases [PubMed, Cochrane Library, Cochrane Library (Trials), Embase and Web of Science Core Collection] were searched from their inception to October 2021 for randomized-controlled trials (RCTs) assessing the biochemical effect of PA on biomarkers in participants with MCI. Pooled effect size was calculated by the standardized mean difference (SMD). Results: A total of 13 RCTs involving 514 participants by reporting 8 inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, -6, -8, -10, -15, C-reactive protein (CRP) and interferon-γ (IFN-γ) and 5 neuroprotective factors (brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF-1), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), irisin] were included. The meta-analysis showed that PA had positive effects on decreasing TNF-α (SMD = - 0.32, 95% CI - 0.58 to 0.07, p = 0.01; I2 = 32%) and CRP (SMD = - 0.68, 95% CI - 1.05 to 0.32, p = 0.0002; I2 = 18%), while significantly improving BDNF (SMD = 0.32, 95% CI 0.09-0.56, p = 0.007; I2 = 42%) and IGF-1 (SMD = 0.42, 95% CI 0.03-0.81, p = 0.03; I2 = 0%). Conclusion: PA had a certain effect on inhibiting inflammatory cytokines but promoting neuroprotective factors in individuals with MCI which may provide a possible explanation for the potential molecular mechanism of PA on cognitive improvement.