<b><i>Background:</i></b> Psychosocial interventions are often used as an adjunct to the medical management of multiple sclerosis (MS). However, the efficacy of such approaches for a range of psychosocial indications remains unclear. <b><i>Objective:</i></b> To determine the efficacy of psychosocial therapies for people with MS (PwMS). <b><i>Methods:</i></b> We searched 6 electronic databases (Medline, Embase, PsycINFO, Cochrane Central Register of Controlled Trials, CINAHL, and Clinicaltrials.gov) until April 21, 2016, for randomized controlled trials reporting the effect of psychological interventions for depressive symptoms, anxiety, pain, fatigue, or health-related quality of life (HRQoL) in PwMS. <b><i>Results:</i></b> The search yielded 356 articles with 13 included studies (<i>n</i> = 1,617). Benefits of psychological interventions were found for depressive symptoms (Cohen’s <i>d</i> = 0.281), anxiety (<i>d</i> = 0.285), fatigue (<i>d</i> = 0.228), and mental (<i>d</i> = 0.398) and total HRQoL (<i>d</i> = 0.444), but not physical HRQoL. There were insufficient studies to meta-analyze posttreatment outcomes for pain. Interventions were more effective for HRQoL for patients with relapsing-remitting MS and when treatment doses were larger. Cognitive behavioral therapy (CBT) was not efficacious for PwMS when considered alone. <b><i>Conclusion:</i></b> Psychosocial interventions have a significant, positive impact across a range of outcomes for PwMS with small, yet consistent, effect sizes. There was some indication that CBT was less efficacious than other interventions. However, this may be due to smaller treatment doses in CBT studies.