Background: Compression socks are a popular feature for runners and are widely advertised by the industry. Limited high-quality evidence has summarized the effects of compression socks during running. We aimed to investigate the effects of wearing compression socks compared with placebo or regular socks during running on physiological parameters, running performance, and perceptual outcomes. Methods: The protocol was registered at PROSPERO (CRD42022330437). Five databases (MEDLINE, Embase, CINAHL, SPORTDiscus, and Web of Science) were searched. Clinical trials exploring the effect of compression socks during running on physiological parameters, performance, and perceptual outcomes were included. The Cochrane risk of bias 2 tool was used to assess the risk of bias. Results: We included 28 trials (600 runners), with 16 trials (284 runners) contributing to meta-analysis. For physiological outcomes (eg, heart rate mean difference [95% CI = 0.82 [−0.39 to 2.03] and blood lactate concentration mean difference [95% CI] = 0.30 [−0.39 to 0.98]), pooled analysis indicated low to moderate-certainty evidence that compression socks do not differ from regular socks. For running performance (eg, running speed mean difference [95% CI] = −0.24 [−0.79 to 0.31] and time to exhaustion standardized mean difference [95% CI] = −0.26 [−0.65 to 0.13]), pooled analysis indicated very low to low-certainty evidence that compression socks do not differ from regular socks. For perceptual outcomes (eg, perceived exertion standardized mean difference [95% CI] = 0.06 [−0.17 to 0.29] and lower limb muscle soreness standardized mean difference [95% CI] = 0.08 [−0.35 to 0.51]), pooled analysis indicated very low to moderate-certainty evidence that compression socks do not differ from regular socks. Conclusion: There is very low to moderate-certainty evidence that wearing compression socks during running does not benefit physiological, running performance, or perceptual outcomes compared with regular socks.