The expression of the transmembrane protein CD44 gradually declines during terminal erythropoiesis, marking the differentiating stages of erythroblasts. Despite its significance, the specific role and functional mechanisms of CD44 in erythropoiesis remain poorly understood. In this study, we found that CD44 knockout (CD44KO) mice displayed bone marrow dyserythropoiesis and an exacerbation of phenylhydrazine-induced hemolytic anemia. Single-cell sequencing analysis revealed activated endoplasmic reticulum (ER) stress in CD44KO erythroblasts. Specifically, the PERK/eIF2α/ATF4/CHOP pathway was upregulated, accompanied by enhanced autophagy and subsequent cell apoptosis. Mechanistically, CD44 deficiency suppressed both the PI3K/AKT/NRF2 and p62/NRF2 pathways, consequently downregulating GPX1 and GPX4 expression, resulting in significantly elevated levels of reactive oxygen species (ROS) and lipid oxidation in erythroid cells. Furthermore, the oxidizing agent HO induced ER stress dose-dependently, inhibiting in vitro erythroid differentiation of mouse fetal liver cells. Notably, CD44KO erythroblasts demonstrated heightened sensitivity to HO treatment. Our findings elucidate the role of CD44 in maintaining redox homeostasis and proteostasis during terminal erythropoiesis, providing valuable insights into how ROS-induced ER stress contributes to pathogenic erythropoiesis.