Introduction: Endoscopic endonasal approaches (EEAs) are routinely used to resect skull base lesion. However, they are laterally restricted when addressing lesions that extend into the petroclival region or lateral brainstem. Research question: Is the endoscopic pre-subtemporal keyhole approach (EPSKA) effective for accessing and treating skull base lesions? Material and methods: Twelve sides of six cadaveric heads were dissected to simulate the EPSKA. This technique combines standard subtemporal keyhole craniotomy with an additional inferomedial subtemporal bone window. Following assessment of the anatomical feasibility, the approach was applied to clinical cases Results: Cadaveric dissections confirmed that the EPSKA provided safe access to critical neurovascular structures within the anterior tentorial incisural space, petroclival region, and ventrolateral surface of the pons. The approach was subsequently applied in ten patients: eight with meningiomas, one with an epidermoid cyst, and one with a cavernous malformation. Gross total resection was achieved in four cases, near total resection in two cases, and subtotal resection in four cases. Postoperative neurological improvement was observed in nine patients. No permanent neurological deterioration or temporal muscle atrophy were observed. Discussion and conclusion: EPSKA provides a safe and minimally invasive corridor for the anterior tentorial incisural space, petroclival region, and ventrolateral pons. Cadaveric validation and clinical application demonstrated that this approach provides sufficient surgical exposure and allows for efficient manipulation of endoscopic instruments, while preserving temporal lobe integrity and minimizing temporalis muscle injury. EPSKA may serve as a valuable surgical option in selected cases that require focused access to deep-seated skull base lesions.