Abstract: To explored the protective effect and mechanism of Chinese yam total protein in human umbilical vein endothelial cells (HUVECs) with high-concentration D-glucose (HG)-induced oxidative stress injury. The HUVECs injury model was established by 50 mmol/L HG. HUVECs were randomly divided into control, model, low-dose Chinese yam total protein (0.5 mg/mL), and high-dose Chinese yam total protein (1 mg/mL) groups. The effects of Chinese yam total protein on the viability, morphology, and angiogenetic ability of HUVECs treated with HG were evaluated. The reactive oxygen species (ROS) level, superoxide dismutase (SOD) and catalase (CAT) activities in cells were determined. The nitric oxide (NO), 8-hydroxy deoxyguanosine (8-OHdG), malondialdehyde (MDA), interleukin-1β (IL-1β), and interleukin-6 (IL-6) levels in culture medium supernatant were measured. Protein expression levels of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X (Bax), thioredoxin-interacting protein (Txnip), NOD-like receptor protein 3 (NLRP3), cleaved Caspase-1, and IL-1β were determined. The results showed that Chinese yam total protein could significantly increased the cell viability of HUVECs treated with HG (P<0.01), improved cell apoptotic morphology, and significantly increased the activities of SOD and CAT (P<0.05, P<0.01) and ratio of apoptosis-related proteins (Bcl-2/Bax), angiogenetic ability and nitric oxide (NO) secretion. Moreover, Chinese yam total protein significantly decreased the levels of ROS, MDA, 8-OHdG, IL-1β, and IL-6 (P<0.05, P<0.01) and the expression levels of inflammation-related proteins (Txnip, NLRP3, cleaved Caspase-1, and IL-1β) (P<0.05, P<0.01). Changes in these indicators showed a significant concentration-dependent manner. The results indicate that Chinese yam total protein may protect against HG-induced oxidative stress by inhibiting the Txnip/NLRP3 signaling pathway, restoring the oxidative balance, and reducing the inflammatory response of HUVECs.