Background: Left undiagnosed and untreated, the association between multiple sclerosis and mental health difficulties significantly increases the multimorbidity risk in these patients. Hence, the purpose of this systematic review and meta-analysis was to estimate the prevalence of neuroticism, depression, and anxiety in MS and to explore the cumulative impact of these psychological factors on the disease expression. Methods: A literature search was conducted on PubMed, Web of Science, Scopus, and Google Scholar databases, according to the PRISMA guidelines. Also, the potential risk of bias was assessed using the AXIS tool. Result: After a rigorous full-text examination, among the 756 identified studies, 22 investigations were considered for the systematic review, and 10 studies were selected for the meta-analysis. The prevalence of neuroticism in the studied population was 24.06% (95% CI: 16.79–33.34), of depression 20.77% (95% CI: 7.67–33.88), while the presence of anxiety was found in 23.94% (95% CI: 6.21–40.36). Conclusions: The main finding of this research confirms that psychiatric disorders often co-occur with MS, impacting the clinical symptoms and life quality of patients living with this illness. For a better understanding of the interaction between personality, depression, anxiety, and the disease symptoms, future research should consider conducting comparisons on more homogenous studies.