Background and purpose: Ferroptosis and parthanatos are two types of programmed cell death associated with cerebral ischemia. There is a sizeable interest in seeking chemical component for the regulation of ferroptosis and parthanatos. Anhydrosafflor yellow B (AHSYB) and hydroxysafflor yellow A (HSYA) mitigated cell death caused by oxidative stress due to antioxidant capacity, yet the mechanism is still uncertain. Thus, we investigated whether AHSYB and HSYA prevent death through these two pathways with the aim to elucidate their potential protective mechanisms of cerebral ischemia. Experimental approach: Oxidative stress model was established by treating PC12 cells with oxygen glucose deprivation and reperfusion (OGD/R). Cellular functions and signaling pathways were analyzed in PC12 cells using cell counting kit-8 (CCK-8), ELISA, transmission electron microscopy (TEM), immunofluorescence, and western blot. Key results: HSYA and AHSYB protected cells from oxidative stress. The phenomenon is associated with ferroptosis and parthanatos. HSYA and AHSYB upregulated cystine/glutamate antiporter system xc- (system xc-) and glutathione peroxidase 4 (GPX4), returned the GSH/GSSG ratio and reactive oxygen species (ROS) to homeostasis, alleviated lipid peroxidation. By reason of reducing ROS, HSYA and AHSYB restrained poly(ADP-ribose) polymerase-1 (PARP-1) overactivation, reduced the production of excess poly(ADP ribose) (PAR) polymer and apoptosis inducing factor (AIF) nuclear translocation. Conclusions and implications: The results suggested that HSYA and AHSYB limited ferroptosis and parthanatos to alleviate oxidative stress in PC12 cells. These findings may have implications for improved understanding of how drugs reduce oxidative stress and develop new strategies for treating degenerative diseases such as cerebral ischemia.