Papaya peels (PP) are discarded after consuming the fruit. However, they contain antioxidants. Oxidative damage caused by free radicals has major implications in many chronic diseases. The objective of this study was to determine in-vitro antioxidant and apoptotic activity of PP extracts. Modulation of endogenous glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), cyclo-oxygenase-2 (COX-2), caspase-3 activities and DNA fragmentation by PP extracts in HepG2 cells were evaluated. Gallic acid (18.06 μg/g), caffeic acid (29.28 μg/g), p-coumaric acid (38.16 μg/g), ferulic acid (95.46 μg/g) and quercetin (3.17 μg/g) were the major polyphenols quantified in PP extracts. In-vitro antioxidant capacity of PP was determined by ferric reducing antioxidant potential (31.86 μM Fe+2/g), trolox equivalent antioxidant capacity (14.56 mM trolox equivalents (TE)/g), oxygen radical scavenging activity (30.88 mM TE/g) and 2,2-diphenyl-1-picrylhydrazyl radical scavenging ability (IC50-8.33 mg/ml). Induction of oxidative stress significantly (p ≤ 0.05) lowered SOD, CAT, GPx, GR activities and GSH levels by 3.1, 1.46, 2.87, 1.34 and 1.32 folds compared to control respectively. However, treating cells with PP extracts significantly (p ≤ 0.05) enhanced SOD, CAT, GPx, GR activities and GSH compared to oxidative stress induced cells. Treating cells with PP extracts significantly (p ≤ 0.05) lowered COX-2 activity, enhanced caspase-3 activity and induced DNA fragmentation, indicating that PP extracts caused cell death by apoptosis. In conclusion, anti-cancer properties of PP extracts may be due to the synergistic effect of free radical scavenging ability, induction antioxidant enzymes and by inducing apoptosis.