Background & Aim: Primary headaches are a common presentation in emergency departments, and the current standard treatments involve the use of NSAIDs and opioids. However, there is growing interest in exploring alternative therapies, such as ketamine, for pain management in headache patients. This study aimed to compare the efficacy of intranasal ketamine with intravenous morphine in patients with acute headache, considering the rapid and painless administration route of intranasal ketamine. Materials and Methods: This double-blind clinical trial was conducted on patients with acute headache who were referred to the emergency departments of Shahid Sadougi and Rahnamon Hospitals in Yazd between 2019 and 2021. Using Simple Random Sampling, patients were divided into two groups: the case group, which received intranasal ketamine, and the control group, which received intravenous morphine. Pain intensity, assessed using the Visual Analogue Scale (VAS), along with side effects, treatment response, need for additional doses, pain relief, treatment failure, SERSDA (Side effects rating scale for dissociative anesthetics), and onset of drug effect were measured and recorded at various time intervals (0, 5, 10, 15, 30, and 60 minutes). Data analysis was performed using the SPSS software. Results: A total of 100 patients with acute headache participated in the study, with half receiving intranasal ketamine and the other half receiving intravenous morphine. After 60 minutes of treatment, the average pain score in the morphine group was 1.95 ± 0.35, while in the ketamine group, it was 1.47 ± 0.34. The ketamine group showed a treatment response (4.73 ± 0.61) within 5 minutes of starting the treatment, whereas the morphine group exhibited a response (4.25 ± 0.52) after 15 minutes. The most common side effects in the morphine group were nausea, dizziness, and hypotension, while burning and irritation of the nasal mucosa, nausea, lightheadedness, and hallucinations were the most common side effects in the ketamine group.Conclusion: Based on the findings of this study, intranasal ketamine demonstrated similar analgesic efficacy to intravenous morphine in the management of acute headaches (after ruling out secondary causes). Moreover, intranasal ketamine exhibited a faster onset of action compared to intravenous morphine. Therefore, intranasal ketamine may be considered a suitable alternative to intravenous morphine for pain management in patients with acute headaches.