Objectives: To examine the immediate and sustained effects of interventions for changing physical activity behavior in people with multiple sclerosis (MS), and to explore factors that might moderate intervention effects on physical activity behavior (eg, intervention type and duration, type of physical activity measurement, intensity of theory integration [degree of theory used in study design], and study quality). Data Sources: Systematic searches were conducted in 4 databases, including MEDLINE, CINAHL, PsychINFO, and Google Scholar, in October 2017 and October 2018. Updated searches were conducted in September 2019 with 2 additional databases (Embase and Scopus) and enhanced search terms. Study Selection: Studies were included that (1) incorporated a randomized controlled trial design of interventions that targeted change in physical activity behavior in adults with MS, namely, exercise training and behavioral intervention (alone and combined); (2) included self-reported and/or device-measured physical activity as an outcome; and (3) contained pre- and post-intervention assessments. Data Extraction: Data were extracted for immediate (pre- to post-intervention) and sustained (pre-intervention to follow-up) physical activity outcomes and study characteristics. Weighted mean effect sizes were expressed as standardized mean differences (SMD). Heterogeneity between each categorical moderator was compared using Q between statistics. Data Synthesis: The mean SMD was 0.56 for immediate changes (n=24) and 0.53 for sustained changes (n=7) of physical activity outcomes. Self-reported physical activity measures yielded larger effects (SMD, 0.64; n=22) than those of device-measured physical activity (0.26; n=7). There appeared to be larger immediate effects of behavioral interventions (SMD, 0.71; n=9) than exercise training (SMD, 0.53; n=7) and combined interventions (0.37; n=8). Conclusions: Current evidence demonstrates that interventions are efficacious for increasing and potentially sustaining physical activity behavior in adults with MS. The effects appear to be optimized based on the delivery of behavioral interventions alone, and these interventions may be capable of supporting long-term behavior change.