Background: Ṣudā‘ (Headache disorder), an incapacitating neurological disorder, negatively impacts people’s quality of life, productivity, family and social life and poses huge financial constraints. Itrifal Mulayyin, is a widely used Unani medication for the treatment of headache disorders. Aim: The present study evaluates the effectiveness and safety of Itrifal Mulayyin in headache patients to validate its ethnomedicinal claims. Methods: Clinically diagnosed headache patients, who fulfilled the inclusion criteria and were willing to participate in the study were recruited after obtaining a duly signed informed consent form. The study was conducted in compliance with Good Clinical Practices (GCP) guidelines, with due approval by the Institutional Ethics Committee. Patients received 7g of Itrifal Mulayyin, orally once daily at bedtime for 7 days. Clinical pathology and biochemistry were done to evaluate the medication safety, alongside monitoring adverse occurrences. The Visual Analogues Scale (VAS) was used to assess the efficacy of the formulation. Results: Twenty of 106 recruited patients were unable to take the test, while 86 patients completed the trial. The mean age of the study population was 35.3 years and the majority of them (70.9%) were female. The overall response to treatment was found to be 85%. After 7 days of treatment with Itrifal Mulayyin, a statistically significant (P<0.05) decrease in the mean VAS score was recorded. Pathological and biochemical indices remain normal and no significant change was observed before and after treatment. Throughout the trial, no AE (adverse events) or drug intolerance were reported. Conclusion: The study results affirm the ethnomedicinal claims of the formulation and indicate that Itrifal Mulayyin may be used orally for the efficient treatment of headaches with little to no risk to medication safety.