Purpose The need for efective treatment for post-dural puncture headache (PDPH) is a growing research entity. This study aimed to test the efectiveness of additional dexmedetomidine (DEX) to PDPH conservative management and evaluate its cerebral hemodynamic efects trans-cranial Doppler. Methods This prospective randomized double-blind controlled trial was conducted on 43 post-partum females sufering 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 efects on cerebral vessels and the occurrence of any adverse efects. Results VAS and Lybecker scores were signifcantly lower in DEX group. The middle cerebral artery mean fow velocity was signifcantly 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 efectively relieved the symptoms and lowered pain scores which could be due to its analgesic and cerebral vasoconstrictive efects. Trial registration This study was approved by the research ethical committee of Faculty of Medicine, Zagazig University with the reference number (ZU-IRB#: 6075/26-4-2020) and it was registered under clinicaltrials.gov (NCT04327726).