Traumatic brain injury is a widespread public health threat that has resulted in millions of deaths and disabilities worldwide. Numerous medicines available provide symptomatic relief but do not stop secondary injury from progressing. Hence, innovative therapeutic agents that protect against neuronal damage following trauma and its associated complications, particularly secondary injury, are needed. The study used a Swiss albino mouse (25-30 g) of either sex. Traumatic brain injury was induced by a weight-drop model, and blood glucose level and systolic blood pressure were observed at different time intervals. The parameters (blood glucose and Systolic blood pressure) were significantly reduced by treatment with zonisamide and Nigella sativa per se and in combination. Comparatively, low blood glucose levels and Systolic blood pressure were observed when zonisamide (100 mg/kg) and NS (300 mg/kg) were co-administered, indicating the potential role of both drugs in the prevention of TBI-induced hyperglycemia and hypertension.