Cerebral venous sinus thrombosis (CVST) is a distinct cerebrovascular disorder, and ~50% of CVST patients progress to cerebral venous infarction, resulting in elevation of cerebral venous pressure. Anticoagulation is the standard initial treatment and is associated with a reduced relative risk of mortality and dependency. Recombinant human soluble thrombomodulin (rhs‑TM) is a promising therapeutic natural anticoagulant comparable to antithrombin, tissue factor pathway inhibitor, and activated protein C. The present study aimed to investigate the protective effects of rhs‑TM in a CVST rat model, and identify any underlying mechanisms. Rats were treated with rhs‑TM intravenously prior to CVST. Following neurological function evaluation, animals were sacrificed and brain water content and infarct volume were assessed. Brain tissue was collected from the infarcted segments and mRNA and protein expression levels of high mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE), tumor necrosis factor (TNF)‑α, interleukin (IL)‑1β, IL‑6, caspase‑3, B‑cell lymphoma‑2 and Bcl‑2 associated X were analyzed by reverse transcription-quantitative polymerase chain reaction and western blot analysis. rhs‑TM significantly prevented neurological deficits in locomotor function and reduced infarct volume. The expression levels of HMGB1‑RAGE were upregulated in the infarcted segments of rat brains following CVST. Pretreatment with rhs‑TM inhibited the HMGB1‑RAGE axis, alleviating the expression levels of the proinflammatory cytokines, TNF‑α, IL‑1β and IL‑6; however, expression levels of the apoptosis-associated genes and proteins remained unaffected. The results of the present study indicated that rhs‑TM protects against CVST in the rat model via inhibition of the HMGB1‑RAGE axis and inflammation, but not via apoptosis.