Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancy of the digestive tract, accounting for 1% of all digestive tract malignancies. GISTs occur most frequently in the stomach, followed by the small intestine and colorectum, and rarely in the mesentery, omentum, and retroperitoneum. Avapritinib’s approval for GISTs in 2020 marks a milestone in precision oncology, showing its significant antitumor activity against the resistant platelet-derived growth factor receptor-alpha D842V mutation. It has a manageable safety profile, with dose adjustments for mitigating side effects without reducing efficacy. Avapritinib-induced subdural hematomas are rare but potentially lethal complications. Our patient had a metastatic small bowel GIST and liver metastases and began avapritinib treatment in January 2024. He had a stable condition until early May. He presented with acute encephalopathy, altered mentation, and left subdural hematoma, which was suspected to be caused by avapritinib, resulting in its discontinuation. Despite receiving diligent care, the patient’s condition did not improve, and he eventually died.