Objectives: Substance use disorder (SUD) is a prevalent health issue with serious personal and societal consequences. This review aims to estimate the effects and safety of Mindfulness-based Relapse Prevention (MBRP) for SUDs. Methods: We searched electronic databases for randomized controlled trials evaluating MBRP for adult patients diagnosed with SUDs. Two reviewers independently assessed citations, extracted trial data, and assessed risks of bias. We conducted random-effects meta-analyses and assessed quality of the body of evidence (QoE) using the Grading of Recommendations Assessment, Development, and Evaluation approach. Results: We identified 9 randomized controlled trials comprising 901 participants. We did not detect statistically significant differences between MBRP and comparators on relapse (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.46-1.13, low QoE), frequency of use (standardized mean difference [SMD] 0.02, 95% CI -0.40 to 0.44, low QoE), treatment dropout (OR 0.81, 95% CI 0.40 to 1.62, very low QoE), depressive symptoms (SMD -0.09, 95% CI -0.39 to 0.21, low QoE), anxiety symptoms (SMD -0.32, 95% CI -1.16 to 0.52, very low QoE), and mindfulness (SMD -0.28, 95% CI -0.72 to 0.16, very low QoE). We identified significant differences in favor of MBRP on withdrawal/craving symptoms (SMD -0.13, 95% CI -0.19 to -0.08, I = 0%, low QoE) and negative consequences of substance use (SMD -0.23, 95% CI -0.39 to -0.07, I = 0%, low QoE). We found negligible evidence of adverse events. Conclusions: We have limited confidence in estimates suggesting MBRP yields small effects on withdrawal/craving and negative consequences versus comparator interventions. We did not detect differences for any other outcome. Future trials should aim to minimize participant attrition to improve confidence in effect estimates.