Background: Migraine headaches are a recurring condition marked by intense and throbbing pain, typically localized to one side of the head. These headaches are frequently accompanied by symptoms like nausea, vomiting, and heightened sensitivity to light and sound. Typically, they persist for a duration ranging from four hours to three days. The current study was conducted to investigate the efficacy and tolerability of sodium valproate versus Amitriptyline in migraine prophylaxis Methods: Patients were included in the study based on predefined inclusion and exclusion criteria. We collected data from 90 outpatient department (OPD) prescription sheets of individuals with migraine who were undergoing prophylactic therapy with either amitriptyline or sodium valproate in the Neurology Department. A record of the patient’s baseline characteristics was maintained in a case record form. Other data collected included the duration of symptoms, frequency of headaches, results of neurological examinations, as well as assessments of migraine pain severity and functional disability. Results: After 3 months, sodium valproate outperformed amitriptyline with a significantly higher percentage of patients experiencing >50% improvement in VAS score (68.29% vs. 50.00%, P = 0.012). The trend continued at 6 months, with sodium valproate surpassing amitriptyline in VAS score improvement (95.12% vs. 71.43%, P = 0.021). In terms of headache severity, a greater proportion of sodium valproate patients had ≥ 1-grade improvement at 3 months (90.24% vs. 76.19%, P = 0.047). Additionally, functional disability improvement was significantly higher for sodium valproate at 3 months (97.56% vs. 90.47%, P = 0.031). Overall, sodium valproate proved more effective in alleviating pain and improving headache and functional disability in migraine patients. Among 83 migraine subjects, 19 in the amitriptyline group and 22 in the sodium valproate group experienced adverse drug reactions. Conclusion: Sodium valproate outperforms amitriptyline in improving pain severity, headache intensity, and functional disability in migraine patients. These findings align with earlier research outcomes. Sedation and weight gain were the most common ADRs associated with both medications. Amitriptyline exhibited a higher incidence of ADRs among patients, particularly after the 6-month mark. The results of this investigation indicate that, for individuals with migraines, sodium valproate may represent a preferable choice over amitriptyline.