BACKGROUND Paradoxical transtentorial herniation is a rare but life-threatening complication of cerebrospinal fluid drainage in patients with large decompressive craniectomy. However, paradoxical transtentorial herniation after rapid intravenous infusion of mannitol has not been reported yet. CASE SUMMARY A 48-year-old male suffered from a right temporal vascular malformation with hemorrhage. In a coma, the patient was given emergency vascular malformation resection, hematoma removal, and the right decompressive craniectomy. The patient woke up on the 1st d after the operation and was given 50 g of 20% mannitol intravenously every 8 h without cerebrospinal fluid drainage. On the morning of the 7th postoperative day, after 50 g of 20% mannitol infusion in the Fowler’s position, the neurological function of the patient continued to deteriorate, and the right pupils dilated to 4 mm and the left to 2 mm. Additionally, computed tomography revealed an increasing midline shift and transtentorial herniation. The patient was placed in a supine position and given 0.9% saline intravenously. A few hours later, the patient was fully awake with purposeful movements on his right side and normal communication. CONCLUSION Paradoxical herniation may occur, although rarely, after infusing high-dose mannitol intravenously in the Fowler’s position in the case of a large craniectomy defect. An attempt should be made to place the patient in the supine position because this simple maneuver may be life-saving. Do not use high-dose mannitol when the flap is severely sunken.