Traditionally in Ethiopia, Clematis Hirsuta leaves have been utilized to prevent diarrhea, tooth infection, and gonorrhea. This particular study aimed to examine the phytochemical composition, as well as the antimicrobial and antioxidant activities of the crude extract (CE), CuONPs, and essential oil (EO) of C. Hirsuta leaves. The synthesis of copper oxide (CuO) nanoparticles from CuSO 4 through the wet chemical precipitation method was characterized using X-ray diffraction (XRD) analysis and scanning electron microscopy (SEM). Both CE, and EO were confirmed to contain phenolics, flavonoids, alkaloids, saponins, steroids, glycosides, terpenoids, and tannins through the phytochemical screening test. The highest amount of TFC 103.5 mg GLA/g was observed in the CE, whereas the lowest value was recorded for EO extracts. The antioxidant activity of each CE, CuONPs and EO was assessed using the DPPH free radical scavenging assay, and it demonstrated the highest antioxidant activity, surpassing that of standard ascorbic acid, which was less than 80%. EO exhibited the highest %inhibition at 80 ppm concentration, which was 94%. The GCMS results indicated that the EO of C. Hirsuta leaves possesses various chemical constituents, such as Pyrimidinone and 1-Hexadecanol, which may be accountable for pharmacological and antioxidant activities. Although the commercial drug demonstrated a higher inhibition zone than the extract, the obtained EO displayed superior antibacterial activity, followed by CuONPs, and CF extract, respectively. In conclusion, these findings suggest that C. Hirsuta leaves are a promising source of natural antioxidant capacity, which could have significant importance as a therapeutic agent in preventing or slowing down the progress of aging-associated oxidative stress related to degenerative diseases, such as diabetes, cancer, and cardiovascular diseases caused by a lack of antioxidant capacity.