An applicable cerebral venous sinus thrombosis (CVST) model is imperative for exploring its pathophysiology. We established a novel severe CVST model using semi-ligation, ferric chloride, and thrombin.A total of 138 male Sprague-Dawley rats were randomly divided into semi-ligation (n = 75) and non-semi-ligation (n = 63) groups. A sham group (n = 46) was also included. We compared short-term and long-term neurological and cognitive dysfunction, mortality rates, thrombus load, venous infarction volume, the blood-brain barrier permeability, brain water content, and microglia activation among the three groups.Thrombi involving multiple venous sinuses appeared in all semi-ligation rats within 2 days postoperatively. Compared with the non-semi-ligation group, short-term and long-term neurological dysfunction were more severe (p < 0.05), and thrombus weight, venous infarction volumes, and microglia activation were more significant (p < 0.05) in the semi-ligation group. Further, the cognitive function of the semi-ligation group significantly decreased (p < 0.05) on postoperative day 21. Cumulative mortality rates between the semi-ligation and non-semi-ligation groups did not differ significantly.Semi-ligation combined with ferric chloride and thrombin can produce a severe CVST model with multiple venous sinus involvement, which is suitable for short- and long-term neurological and cognitive dysfunction assessment.© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.