To systematically evaluate the effectiveness and safety of ketamine in preventing propofol injection pain (PIP). The electronic databases including PubMed, Embase, Web of Science, and Cochrane Library were searched from their inception until 2 August 2023. Randomized controlled trials (RCT) comparing ketamine with placebo or other interventions to alleviate PIP in adults were included. Fixed-effects or random-effects models were used to calculate pooled risk ratios (RR) and corresponding 95% confidence intervals (CI) based on the heterogeneity of the studies included. Thirteen RCTs involving 2105 patients were included. In terms of reducing the incidence of PIP, ketamine is more effective than placebo (RR = 0.43, 95% CI = [0.34, 0.55], P < 0.00001), lidocaine (RR = 0.70, 95% CI = [0.55, 0.90], P = 0.005), dexmedetomidine (RR = 0.52, 95% CI = [0.40, 0.66], P < 0.00001), and thiopental (RR = 0.25, 95% CI = [0.08, 0.83], P = 0.02). In reducing the incidence of severe PIP, ketamine is superior to placebo (RR = 0.12, 95% CI = [0.08, 0.19], P < 0.00001), and lidocaine (RR = 0.34, 95% CI = [0.21, 0.56], P < 0.0001), except dexmedetomidine (RR = 0.20, 95% CI = [0.04, 1.13], P = 0.07), and thiopental (RR = 0.33, 95% CI = [0.04, 3.10], P = 0.33). Compared with mixed injection, separate injection of ketamine and propofol showed no significant difference in the incidence of PIP (RR = 0.96, 95% CI = [0.31, 3.00], P = 0.95) and severe PIP (RR = 1.19, 95% CI = [0.07, 21.29], P = 0.90). Based solely on the reports from the studies included, subanesthetic doses of ketamine are generally safe in preventing PIP. A subanesthetic dose of ketamine can effectively and safely reduce the incidence of PIP and severe PIP in adults, and is more effective than lidocaine, dexmedetomidine, and thiopental. PROSPERO CRD42023455093.