Multiple sclerosis (MS) is a complex, demyelinating disease of the central nervous system. Fatigue is commonly reported by people with MS (PwMS). MS-related fatigue severely affects daily activities, employment, socioeconomic status, and quality of life.We conducted this systematic review and meta-analysis to determine whether psychological interventions are effective in managing fatigue in PwMS.We performed systematic searches of Medline, EMBASE, PsycINFO, and CINAHL to identify relevant articles published from database inception to April 5, 2017. Reference lists from relevant reviews were also searched.Two independent reviewers screened the papers, extracted data, and appraised the included studies. A clinical psychologist verified whether interventions were psychological approaches. A narrative synthesis was conducted for all included studies. For relevant randomized controlled trials that reported sufficient information to determine standardized mean differences (SMDs) and 95% confidence intervals (CIs), meta-analyses were conducted using a random-effects model.Of the 353 identified articles, 20 studies with 1,249 PwMS were included in this systematic review. Narrative synthesis revealed that psychological interventions reduced fatigue in PwMS. Meta-analyses revealed that cognitive behavioral therapy decreased levels of fatigue compared with non-active controls (SMD = -0.32; 95% CI: -0.63 to -0.01) and compared with active controls (relaxation or psychotherapy) (SMD = -0.71; 95% CI: -1.05 to -0.37). Meta-analyses further showed that both relaxation (SMD = -0.90; 95% CI: -1.30 to -0.51), and mindfulness interventions (SMD = -0.62; 95% CI: -1.12 to -0.12), compared with non-active control, decreased fatigue levels. The estimates of heterogeneity for the four meta-analyses varied between none and moderate.This study found that the use of psychological interventions for MS-related fatigue management reduced fatigue in PwMS. While psychological interventions are generally considered first-line therapy for MS-related fatigue, further studies are needed to explore the long-term effect of this therapy.