Protein fibrillation and oxidative damage are closely associated with the development of many chronic diseases such as Alzheimer’s disease, Parkinson’s disease and transthyretin amyloidoses. This work aimed at evaluating the fibrillogenic, antioxidant, anti-oxidative, hemolytic and cytotoxic activities of phenolic-rich extract from Chromolaena odorata (L) R.M. King & H. Rob aerial parts (COPE). As revealed by Thioflavin-T fluorescence, transmission electron microscopy, NBT redox cycling and ANS fluorescence analyses, COPE suppressed the fibril formation of hen egg-white lysozyme by directly binding to the protein and preventing surface exposure its of hydrophobic clusters. In addition, COPE demonstrated potent radical scavenging activities against DPPH˙ and ABTS˙⁺, chelated ferrous ions, and inhibited metal-catalyzed oxidation of bovine serum albumin. The observed effects could be explained by the high content of flavonoids (22.82 QE/g) and phenolics (190 mg GAE/g) present in COPE. UHPLC-ESI-QTOF-MS/MS analysis of COPE in negative ionization mode revealed that the predominant compounds were phenolics and terpenoids. Furthermore, COPE was found to exert very minimal cytotoxic effects against human red blood cells (≤ 5% hemolysis) and human embryonic kidney (HEK-293) cells (≥ 80% viability). These findings suggested that with further investigations, phenolic-rich extract from C odorata could be effectively valorized for pharmacological applications against protein fibrillogenic and oxidative damage related conditions.