Cerebral venous sinus thrombosis (CVST) is a rare, serious, and complex cerebrovascular disease. The prothrombin G20210A mutation is the second most common inherited thrombophilia and is considered to be one of the etiologies of CVST. The optimal heparinoid medication for treatment remains a topic of debate. This case report describes a young woman with CVST who did not respond to low-molecular-weight heparin (LMWH). The patient was initially treated with LMWH; however, her symptoms and clot burden in the sagittal sinus worsened, and coagulation studies showed no evidence of therapeutic anticoagulation despite good compliance. Unfractionated heparin was then initiated, and the patient's symptoms improved dramatically within 24 hours, along with the recanalization of the cerebral venous sinuses. Genetic testing revealed a heterozygous mutation in the prothrombin gene (G20210A). This mutation is a known risk factor for CVST. However, it is unclear why the patient did not respond to LMWH but responded appropriately to unfractionated heparin. This case report highlights the potential for LMWH resistance in patients with CVST and prothrombin gene mutations. These findings also emphasize the importance of close monitoring of coagulation parameters and clinical response in patients with CVST receiving LMWH.