Introduction Non - traumatic headaches are one of the most common causes of referral to hospital emergency. This study aimed to compare the efficacy of intranasal ketamine and intravenous ketorolac on acute non-traumatic headaches. Methods This randomized and double-blind clinical trial was conducted in 2019. One hundred and forty samples were randomly divided into intranasal ketamine (A) and intravenous ketorolac (B). Group (A) received ketamine intranasal (0.75 mg/kg, max 75 mg), and group B received intravenous ketorolac (30 mg). Headache severity was measured on arrival, 30, 60, and 120 min after intervention with Visual Analogue Scale (VAS). The side effects were recorded an hour after the intervention. Result The mean difference of pain intensity 30, 60, and 120 min after the intervention between the two groups was statistically significant (p < 0.001). In the first 30 min, significant changes were observed in the VAS levels of the two groups. These changes were significantly greater in the intranasal ketamine group (p < 0.001). Side effects such as fatigue, dizziness, general discomfort, nausea, increased heart rate, and hypertension were significantly higher in the ketamine group (p < 0.05). Conclusion Intranasal ketamine and intravenous ketorolac both effectively reduced headaches. However, more analgesic effects of intranasal ketamine in a short time can be considered as a selective approach to reducing headaches. Trial registration IRCT20180108038276N3, Registered 29 September 2019. Ethics committee reference number IR.KUMS.REC.1398.068.