The cost and worrisome toxicities associated with currently available anti-inflammatory drugs necessitate continuous search for more effective, cheap, and safe anti-inflammatory agents. This study investigated the anti-inflammatory and analgesic activities of ethanol extract of Hymenodictyon pachyantha stem bark (EEHP). The anti-inflammatory activity of EEHP was evaluated by determining its effect on egg albumin–induced rat paw edema, phospholipase A2 (PLA2) activity, calcium chloride (CaCl2)–induced platelet aggregatory response, and membrane stabilization. The effect of EEHP on acetic acid–induced writhing responses was used as a model for analgesic property. The presence of flavonoids, terpenoids, steroids, saponins, alkaloids, tannins, and phenols was detected in EEHP. There was no sign of toxicity and mortality 24 h post-EEHP administration, suggesting that it is safe up to 5000 mg/kg b.w. EEHP significantly inhibited egg albumin–induced rat paw edema, in a dose-dependent manner and in both early and late stages of inflammation. Similarly, EEHP significantly inhibited PLA2 activity and platelet aggregatory response. EEHP also inhibited hypotonic-induced haemolysis by 23.99, 54.99, and 92.68% at 0.2, 0.6, and 1.0 mg/ml respectively. Similarly, EEHP produced 44.64, 58.04, and 70.54% reduction in the number of writhings induced by acetic acid at 200, 400, and 600 mg/kg p.o. respectively. These results demonstrated that EEHP has analgesic and anti-inflammatory effects. The results also showed that the mechanisms of the anti-inflammatory effect may be by inhibiting PLA2 and aggregation of platelets, and stabilization of lysosomal membrane.