Abstract Objective: To evaluate the efficacy and safety of trans-nasal Sphenopalatine Ganglion (SPG) block over other treatments for Post-Dural Puncture Headache (PDPH) management. Methods: A systematic literature search was conducted on databases for Randomized Controlled Trials (RCTs) comparing trans-nasal SPG blockade for the management of PDPH over other treatment modalities. All outcomes were pooled using the Mantel-Haenszel method and random effect model. Analyses of all outcomes were performed as a subgroup based on the type of control interventions (conservative, intranasal lignocaine puffs, sham, and Greater Occipital Nerve [GON] block). The quality of evidence was assessed using the GRADE approach. Results: After screening 1748 relevant articles, 9 RCTs comparing SPG block with other interventions (6 conservative treatments, 1 sham, 1 GON and 1 intranasal lidocaine puff) were included in this meta-analysis. SPG block demonstrated superiority over conservative treatment in pain reduction at 30 min, 1 h, 2 h, 4 h after interventions and treatment failures with “very low” to “moderate” quality of evidence. The SPG block failed to demonstrate superiority over conservative treatment in pain reduction beyond 6 h, need for rescue treatment, and adverse events. SPG block demonstrated superiority over intranasal lignocaine puff in pain reduction at 30 min, 1 h, 6 h, and 24 h after interventions. SPG block did not show superiority or equivalence in all efficacy and safety outcomes as compared to sham and GON block. Conclusion: Very Low to moderate quality evidence suggests the superiority of SPG block over conservative treatment and lignocaine puff for short-term pain relief from PDPH. PROSPERO Registration: CRD42021291707.