Context: Genistein (Gen) has shown protective effects against ageing process., Objective: To explore the role of Gen on the senescence of H 2 O 2 -induced human umbilical vein endothelial cells (HUVECs) and investigate the possible mechanism., Materials and Methods: HUVECs were treated with different concentrations of H 2 O 2 (50, 100, 200 and 400 μmol/L) for 1 h or Gen administration (20, 40, 80 and 160 μg/mL) for 24 h. Functional experiments (cell counting kit-8, β-galactosidase staining and flow cytometry) were used to detect the effect of Gen on H 2 O 2 -induced HUVECs. After HUVECs were transfected with TXNIP overexpression plasmids, the expression of p16, p21, thioredoxin-interacting protein (TXNIP), nucleotide-binding and oligomerization domain-like receptor 3 (NLRP3), cleaved caspase-3 and cleaved caspase-1 in HUVECs were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot., Results: H 2 O 2 (200 and 400 μmol/L) inhibited the proliferation of HUVECs. At concentrations of >50 μmol/L, H 2 O 2 induced the cell cycle progression arrests in G1 phase and promoted cell senescence of HUVECs. Gen had no obvious cytotoxicity to HUVECs below 160 µg/mL. H 2 O 2 -induced HUVEC senescence and the expression of TXNIP and NLRP3 in HUVECs were down-regulated by Gen (40 and 80 µg/mL). Expressions of TXNIP and NLRP3 in HUVECs were up-regulated by H 2 O 2 but down-regulated by Gen. Overexpressed TXNIP partially reversed the suppressive effect of Gen on H 2 O 2 -induced senescence and apoptosis of HUVECs. Expressions of p16, p21, TXNIP, NLRP3, cleaved caspase-3 and cleaved caspase-1 in H 2 O 2 -treated HUVECs were inhibited by Gen, while the inhibition as such was partially reversed by overexpressed TXNIP., Discussion and Conclusions: H 2 O 2 -induced HUVEC senescence was alleviated by Gen via suppressing the TXNIP/NLRP3 axis, which may offer a potential therapeutic approach for improving HUVEC senescence and provide a new direction for the treatment of cardiovascular disease.