Purpose Post-dural puncture headache (PDPH) may be resulted from significant changes in cerebral blood flow, which could be visualized by Transcranial Doppler (TCD). This study was performed to investigate if TCD can be used to predict the occurrence of PDPH in high-risk patients. Methods This prospective observational study was conducted on ninety ASA I and II pregnant females undergoing elective cesarean section (CS) under spinal anesthesia. TCD was performed to all patients within 24 h before the operation, at 24 h and 48 h in the post-operative period to measure mean velocity (MV) and Gosling pulsatility index (PI) in the right middle cerebral artery. For 5 days postoperatively, all patients were assessed and the PDPH patients were identified, their pre- and post-puncture TCD measurements were compared with the corresponding measurements of PDPH-free patients and ROC analysis was done to evaluate the predictive value of TCD parameters. Results 17 patients (18.8%) developed PDPH. PDPH group was significantly higher regarding MV and significantly lower with regard to PI at all times except for the pre-spinal PI. The MV values in all patients showed statistical significant increase within the first 48 h after CS as compared with those before delivery. In PDPH group there was high statistical significant decrease in PI values at 24 h and 48 h compared to the pre-puncture values. The pre-puncture MV was the parameter of the best accuracy for predicting PDPH with a cutoff of MV > 68.4 cm/s and the post-puncture PI at 24 h was the best predictive of PDPH with a cutoff value of < 0.75. Conclusion TCD might prove a useful tool in predicting PDPH suggesting that higher pre-puncture MV with a cutoff value > 68.4 cm/s and post-puncture lower PI at 24 h with a cutoff < 0.75 are the best predictive parameters. Trial registration This clinical trial was registered with ClinicalTrials.gov (NCT03464253).