Leaves of Euphorbia heterophylla (Milk weed) is frequently used in herbal medicine for curing of several conditions in many parts of Nigeria. The study was aimed at elucidating the leaves’ anti-inflammatory potentials and mechanisms of action. The leaves were assessed for their phytochemical contents. The in vitro anti-inflammatory activities of methanol extract of the leaves were evaluated for inhibition of albumin denaturation, proteinase inhibitory activity, membrane stabilization, and anti-lipoxygenase activity, which are associated with inflammatory processes. Aspirin, diclofenac sodium and indomethacin were used as standard drugs. Phytochemical analyses indicated the presence of high concentrations of alkaloids, saponin, and flavonoids; low concentrations of phenol and tannin, with a ferric reducing antioxidant power of 10.7 mg GAE/g. The methanol extract of the leaves significantly inhibited albumin denaturation and proteinase activity, stabilized membrane of red blood cells from hemolysis in heat and hypotonic conditions, and inhibited lipoxygenase activity. The overall results suggest that E. heterophylla is a prospective source of anti-inflammatory agents.