Background: Hemorrhoids are rectoanal venous plexus swelling that causes inflammation, pain, and bleeding. Plants with phenolic compounds are known to improve venous tone and anti-inflammation. Soursop leaves (Annona muricata L.) known contain phenolic compounds and have been used to cure inflammation. However, studies on anti-inflammatory soursop leaves for hemorrhoids are still limited. Objective: This study aims to analyze the effect of Soursop Leaves Ethanol Extract (SLEE) on the histopathological features and expression of COX-2 and TNFα in rectoanal tissue. Method: Swiss mice 20 weeks induced 3 times with 6% croton oil through the anus. SLEE doses of 100, 200, and 400 mg/Kg and aspirin as a positive control were given orally for 7 days. Histopathological examination of the rectoanal tissue of mice was assessed by counting cell necrosis, inflammation, vasodilation, and edema using hematoxylin-eosin. Positive cells expressing COX-2 and TNFα were counted on inflammatory epithelial cells using immunohistochemistry. Results: Administration of SLEE at all doses showed different levels of inflammation, necrosis, vasodilatation and edema in histopathology of rectoanal tissue P <0.00. All three doses of SLEE show significant anti-inflammatory effects on hemorrhoidal tissue. SLEE doses of 200, 400 mg/Kg significantly decreased COX-2 P <0.05 compared to negative controls, and SLEE doses of 100, 200, and 400 mg/Kg significantly decreased TNFα P <0.05 compared to negative controls. Conclusions: SLEE can reduce inflammation and has the potential to be developed as a natural remedy for hemorrhoids.