Objective: To examine the effects of mindfulness- and acceptance-based interventions (MABIs) on reducing symptoms in individuals with multiple sclerosis (MS). Data Sources: A comprehensive search was conducted within the PubMed, CINAHL, PsycINFO, and SCOPUS databases for articles published from inception to July 3, 2020. Study Selection: Randomized controlled trials (RCTs) were included if MABIs were provided to individuals with MS exclusively, with reported pre-and posttest results in symptoms of depression, anxiety, stress, fatigue, or pain. Data Extraction: Characteristics of the included RCTs and data for meta-analysis were extracted. The quality of the included RCTs was assessed using the Cochrane Collaboration risk of bias tool. Data Synthesis: A random effects model with the inverse variance method was used with effect size reported as standardized mean difference. Heterogeneity was assessed using the I 2 statistic. Results: Twenty-three RCTs met the eligibility criteria. Meta-analyses found large effects of MABIs on reducing depressive symptoms, anxiety, stress, and pain, as well as a moderate effect of MABIs on reducing fatigue at the immediate posttest. Large effects of MABIs on reducing depressive symptoms, anxiety, and stress at follow-up were also found, whereas a moderate effect on reducing fatigue was found at follow-up. There was no significant effect of MABIs on reducing pain at follow-up. Conclusions: Fewer studies were included in meta-analyses for pain at the immediate posttest and follow-up and stress and fatigue at follow-up. The overall risk of bias was unclear. Future high-quality studies with follow-up evaluations are needed to support effects of MABIs on reducing symptoms in individuals with MS and examine intervention features that increase and maintain effects. Archives of Physical Medicine and Rehabilitation 2021;000:1−14