Abstract Purpose The need for effective treatment for post-dural puncture headache (PDPH) is a growing research entity. This study aimed to test the effectiveness of additional dexmedetomidine (DEX) to PDPH conservative management and evaluate its cerebral hemodynamic effects trans-cranial Doppler. Methods This prospective randomized double-blind controlled trial was conducted on 43 post-partum females suffering from PDPH with visual analog score (VAS) ≥ 4 and Lybecker score ≥ 2. The study subjects were allocated into control group [n = 22] received nebulization of 4 mL 0.9% saline and DEX group [n = 21] received nebulization of 1 µg/kg DEX diluted in 4 mL 0.9% saline twice daily that was continued until achieving VAS score ≤ 3 and Lybecker score < 2 and/or for a maximum of 72 h. Both groups received routine conservative management. The primary outcome was the VAS and Lybecker scores and the secondary results were the DEX effects on cerebral vessels and the occurrence of any adverse effects. Results VAS and Lybecker scores were significantly lower in DEX group. The middle cerebral artery mean flow velocity was significantly lower, and the pulsatility index was considerably higher after DEX nebulization compared to placebo. Two patients in the control group were indicated for epidural blood patch. Conclusion The addition of DEX nebulization (1 µg/kg twice daily) to the PDPH conservative care effectively relieved the symptoms and lowered pain scores which could be due to its analgesic and cerebral vasoconstrictive effects.