Seedpod, the nonedible portion of lotus (Nelumbo nucifera Gaertn.), was reported to be rich in polyphenols. The objective of this study was to investigate the major bioactive polyphenols of the lotus seedpods. The total polyphenol content (TPC) from ethanol extract of lotus seedpod (PELS) was found to be 34.23 μg gallic acid equivalents (GAE)/mg extract. Four polyphenolic compounds were identified in the PELS, comprised of one flavan‐3‐ol (catechin) and three flavonoids (kaemferol, quercetin and hyperoside). In vitro antioxidant and antiproliferative properties of the PELS were evaluated. PELS exhibited 89.38%, 99.82%, 68.25%, and 95.82% scavenging activities against 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH), superoxide, hydroxyl, and 2,2ʹazinobis‐3‐ethylbenzothiazoline‐6‐sulfonic acid (ABTS) radicals, respectively, at 1.6 mg/ml. The Fe³⁺ reducing power of PELS was 0.605 at 0.32 mg/ml, which is comparable to glutathione (GSH). The PELS showed 31.79% metal chelating capacity and 87.79% inhibition of linoleic acid auto‐oxidation at 1.6 mg/ml. PELS showed cytotoxicity toward HepG2 and LNcap cell lines in vitro with IC₅₀ values at 44.59 and 11.50 μg/ml, respectively. The findings of this study provide evidences that the inedible lotus seedpod could be a source for natural antioxidants and anticancer agents.