Patients with multiple sclerosis (MS) often experience reduced health-related quality of life and mental health comorbidity. The prevalence of insomnia disorder and sleep quality impairments in MS patients ranges from 47% to 62%. Nevertheless, these problems often remain underdiagnosed and undertreated. This review systematically and critically assesses evidence from randomized clinical trials which evaluated the efficacy of different clinical interventions targeting mental and general health in patients with MS on insomnia symptoms and sleep quality. Pubmed, PsycINFO and Medline databases were systematically searched. Eligible studies included adults ≥ 18 years with MS diagnosis; were randomized clinical trials; and reported pre and post-treatment data for primary or secondary outcomes. Nine studies were selected including 755 adults with an MS diagnosis. Studies evaluated the efficacy of various treatments: psychological interventions (5); pharmacotherapy, including medications for fatigue, cannabis extract and melatonin (3); energy conservation therapy (1). Preliminary support was found for psychological interventions and cannabis extract. This work highlights the important need for more high-quality randomized controlled trials for interventions targeting insomnia in MS patients.