Introduction: Cerebral malaria is the most severe complication of Plasmodium falciparum infection. The pathophysiology of cerebral malaria is still unclear, but it is expected caused by cytoadherence, rosetting, autoagglutinations and abundant pro-inflammatory response that will induce the release of secondary molecules like ubiquitin, HIF-1, VEGF, and iNOS. Aim: To determine the effect of Artesunate and brotowali extract (Tinospora crispa) against the expression of ubiquitin, HIF-1α, VEGF and iNOS in the brain of cerebral malaria mice model. Methods: An experimental study of post-test only control group using CB57BL/6J mice model malaria had been done. Samples were divided into 7 groups: negative control (K-), positive control (K+), Artesunate 32 mg/BWkg/ day (P1), Tinospora crispa 70 mg/BWkg/day (P2), combination Artesunate and Tinospora crispa dose 50 mg/ kgBW (P3), combination Artesunate and Tinospora crispa dose 60 mg/kgBW (P4) and combination Artesunate and Tinospora crispa dose 70 mg/kgBW (P5). Mice model were decapitated at 7th day after infection. Expression of ubiquitin, HIF-1α, VEGF, and iNOS was measured by immunohistochemistry. Result: One Way ANOVA showed different expression of ubiquitin, HIF-1α, VEGF and iNOS among groups. Tukey test showed, there was no significant difference in expression of ubiquitin, VEGF and iNOS among single therapy (Artesunate or Tinospora crispa) with combination therapy (p>0.05). Expression of HIF-1α were significantly different between single therapy (Artesunate or Tinospora crispa) with combination therapy of Artesunate and Tinospora crispa 60 mg/kgBW (p=0.019, p=0.013) and combination therapy of Artesunate and Tinospora crispa 70 mg/kgBW (p=0.034; p=0.023). Pearson correlation showed negative correlation between Tinospora crispa dose and expression of HIF-1α (p=0.001; r=-0.832) and iNOS (p=0.001, r=-0.874). Conclusion: The combination of Artesunate and brotowali (Tinospora crispa) extract generally decreases Ubiquitin, HIF-1 α, VEGF dan iNOS expression of cerebral malaria model although only brain HIF-1α expression gives significant decreasing.