The clinical management of inflammatory diseases often relies on NSAIDs and selective COX-2 inhibitors, which shift the arachidonic acid pathway towards 5-LOX, leading to the production of cysteinyl-leukotrienes associated with cancer and inflammation. To develop more effective and safer anti-inflammatory medications, dual inhibitors targeting both COX-2 and 5-LOX are being pursued. Vernonia amygdalina a medicinal plant in the Asteraceae family, historically used for treating skin infections and inflammatory diseases, was investigated in this study. It focused on screening V. amygdalina leaf organic extracts in vitro to develop anti-inflammatory agents by assessing their inhibitory effects on 5-Lipoxygenases, Cyclooxygenase-1, and Cyclooxygenase-2 enzymes. The study involved successive Soxhlet extraction of powdered dried leaves using solvents of varying polarity (from Diethyl ether to Ethanol). The resulting extracts were evaluated for in vitro anti-inflammatory activity through ELISA assays. Results showed that the ethanolic leaf extract of V. amygdalina (VALET) exhibited significant 5-LOX inhibition (71.63% at 100 µg/ml) with an IC50 of 52.99 µg/ml and potent COX-2 inhibition (69.84% at 100 µg/ml) with an IC50 of 41.35 µg/ml, demonstrating one-fold COX-2 versus COX-1 inhibition. This activity was attributed to the presence of secondary metabolites like flavonoids, tannins, and polyphenolic compounds. In conclusion, V. amygdalina ethanolic leaf extracts represent a promising source for dual inhibitory compounds against 5-LOX and COX-2, highlighting the potential of traditional remedies in managing inflammatory diseases and cancers