S-adenosylmethionine (SAMe) is a natural compound used to improve mood-related symptoms. Our aim was to determine the efficacy, safety, and optimal dose of SAMe in Central Nervous System (CNS) signs (e.g., mood, behavior). We conducted a PRISMA-based systematic review by searching PubMed, CINAHL, and Web of Science using MeSH search terms. Articles were independently reviewed by two researchers (with a third resolving conflicts) during title/abstract screening and full-text review. Data were extracted in the same approach, with a quality assessment of included articles. Out of 1881 non-duplicated studies, 36 were included in the review focusing on CNS signs (mood, behavior, sleep). Most studies (n = 32) achieved a 4 or 5 out of 5 points, indicating high study quality. Overall, SAMe was effective in 24 of 36 studies, with adverse events mostly consisting of mild, transient gastrointestinal disturbances. Many patients in these studies did experience improvements in CNS signs from using SAMe alone or in combination with existing therapy. However, future studies are needed to further understand the long-term effects of SAMe in the CNS.