This study investigates the potential protective role of annexin A1 (ANXA1) in cell models of HO-induced Alzheimer's disease. PC12 cells exposed to varying concentrations of HO exhibited a dose-dependent decrease in cell viability. HO exposure led to elevated reactive oxygen species (ROS) levels, reduced superoxide dismutase (SOD) and catalase (CAT) activities, and a decline in ANXA1 protein expression. Under oxidative stress, ANXA1 overexpression increased cell viability, reduced apoptosis rate, enhanced the expression of microtubule-associated protein 3 (LC3) II/I while reducing phosphorylated calcium/calmodulin-dependent protein kinase II (p-CAMK2)/CAMK2 and phosphorylated beclin 1 (p-BECN1)/BECN1. Conversely, ANXA1 knockdown produced contrasting effects. Overexpression of ANXA1, accompanied by administration of KN-93 (a competitive inhibitor of CAMK2), can synergistically diminished p-CAMK2/CAMK2 and p-BECN1/BECN1 levels while significantly increasing LC3 II/I levels, autophagosomes, and autolysosomes. In conclusion, ANXA1 demonstrated a protective role in HO-induced oxidative stress damage model in PC12 cells by inhibiting the CAMK2/BECN1 signaling pathway and enhancing autophagy.