Purpose <p>We aimed to evaluate the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treating cerebellar mutism syndrome (CMS).</p> Methods <p>We retrospectively reviewed all pediatric patients who underwent a posterior fossa tumor resection between May 2007 to September 2022 at a single quaternary pediatric hospital. We evaluated clinical presentation and hospital course, including imaging findings, pathology, and surgical approaches. Propensity score matching was used to compare the symptom duration of patients who received SSRIs versus those who did not.</p> Results <p>A total of 292 patients met the criteria with 25% (<i>n</i> = 73) being diagnosed with CMS. Several factors were significantly associated with a CMS diagnosis, such as pre-operative hydrocephalus (<i>p</i> = 0.002), a vermis-splitting approach (<i>p</i> = 0.007), tumor in the fourth ventricle (<i>p</i> = 0.010), medulloblastoma diagnosis (<i>p</i> = 0.009), and postoperative complication (<i>p</i> &lt; 0.001). Of the patients diagnosed with CMS, 32.9% (<i>n</i> = 24) received SSRI treatment, specifically fluoxetine (<i>n</i> = 18) and sertraline (<i>n</i> = 6). Overall, treatment did not decrease the duration of CMS symptoms or shorten the inpatient rehab course compared to matched controls. However, within the cohort of fluoxetine-treated patients, earlier initiation of medication was significantly correlated with a shorter duration of mutism (<i>p</i> = 0.007).</p> Conclusions <p>We report the largest cohort of CMS patients treated with SSRIs. The lack of overall clinical benefit when compared to untreated patients in our study may be due to the length of delay in starting an SSRI, since early initiation of fluoxetine correlated with shorter CMS symptoms. These results support the importance of early clinical detection of CMS and potentially treating CMS early in the patient’s postoperative course.</p>