Introduction: Research on bioactive compound isolations, descriptions, and biological tests on medicinal plants is still limited. This study primarily explores the secondary bioactive metabolites and the pharmacological potential of four medicinal plants from Ethiopia. The study aimed to screen phytochemical constituents and investigate their antioxidant and anti-inflammatory potential. Methods: The ethanolic extracts of Clerodendrum myricoides (Hochst.) R.Br. ex Vatke, Millettia ferruginea (Hochst.) Hochst. ex Baker, Vepris dainellii (Pic.Serm.) Kokwaro, and Fuerstia africana T.C.E.Fr. r. leaves were subjected to Ultra Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry (UPLCQTOF-MS)/MS for phytochemical analysis and assays, including anti-oxidant (2,2-diphenyl-1-picrylhydrazyl [DPPH], ferric reducing-ion reducing power [FRAP]), Cyclooxygenase 2 (COX-2) inhibition for anti-inflammatory, and Folin-Ciocalteu for phenolic contents determination. Results: The total phenolic contents of C. myricoides, M. Ferruginea, V. dainellii, and F. africana were 125.68 +/- 0.82 mg, 54.97 +/- 0.94, 113.57 +/- 0.99 and 66.40 +/- 1.14 mg GAE/g, while flavonoid contents were 236.25 +/- 1.85, 78.12 +/- 0.96, 51.148 +/- 1.09 and 60.79 +/- 0.47 mg RE/g, respectively. C. myricoides and F. africana have higher DPPH scavenging rates with IC50: 1.10 +/- 0.12, 2.09 +/- 0.14, mg/ml. C. myricoides and F. africana displayed the highest FRAP values with 33.30 +/- 0.92 and 23.87 +/- 1.42 mM Fe2+/g. F. africana exerted highest anti-inflammatory activities with COX-2 inhibition at IC50 of 1.82 +/- 0.04 mu g/ml. About 61 bioactive metabolites are identified. Alkaloids, phenolic, flavonoids, and terpenoids were the dominant class of identified compounds. Conclusions: The pharmacological tests have validated the therapeutic uses of traditional medicinal plants. Bioactive metabolites play a crucial role in the potential therapeutic applications of plants.