Aim To investigate the effect of saikosaponin A on oxidative stress and ferroptosis of human umbilical vein endothelial cells (HUVEC) induced by hydrogen peroxide (H₂O₂). Methods The oxidative injury model in HUVEC was established and cells were divided into control group, model group, saikosaponin A low-dose, medium-dose and high-dose groups. CCK-8 assay was used to detect cell viability. The levels of malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD) were detected by the kit assay. qRT-PCR was used to detect the mRNA levels of glutathione peroxidase 4(GPX4) and acyl-CoA synthetase long chain family member 4(ACSL4). The protein expression of GPX4 and ACSL4 were detected by Western blot. Results Compared with the control group, the survival rate of HUVEC, GSH level and SOD activity in H₂O₂ group were significantly decreased (P＜0.05), the level of MDA was significantly increased (P＜0.05), the expressions of GPX4 mRNA and protein were significantly decreased (P＜0.05), the expressions of ACSL4 mRNA and protein were increased (P＜0.05). Compared with the model group, saikosaponin A dose-dependently increased the survival rate of HUVEC, inhibited oxidative stress, improved the activity of SOD and GSH level (P＜0.05), and decreased the level of MDA (P＜0.05); In addition, saikosaponin A inhibited ferroptosis in a concentration-dependent manner, up-regulated the expression of GPX4 mRNA and protein(P＜0.05), and decreased the expression of ACSL4 mRNA and protein (P＜0.05). Conclusion Saikosaponin A can protect HUVEC from oxidative stress and ferroptosis induced by H₂O₂.