Mulberry leaf extract has exerted better antidiabetic activities, while the effects of major active components in mulberry leaf extract are still unclear. Cryptochlorogenic acid (CCA) as the major active component in mulberry leaf extracts was investigated herein. Rats were treated with 50mg/kg streptozotocin for the establishment of diabetic model in vivo, and cells were treated with 33.3 mM glucose for the establishment of cell model in vitro. HE staining assay was performed for observation of pancreatic pathology and aldehyde fuchsin staining assay for examining islet cell numbers. The iron content was detected via Perls staining assay with iron assay kit (ab83366). The malondialdehyde (MDA), glutathione (GSH) and oxidized glutathione (GSSG) were detected by corresponding kits. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed for assessment of gene level and Western blot for measurement of protein expression level. The cell survival was detected via CCK-8 assay. The blood glucose level, iron content, accumulation of lipid peroxides and islet injury in diabetic model were all improved by CCA via a concentration-dependent manner. CCA functions via inhibition of ferroptosis by activation of cystine/glutamate transporter system (XC-)/glutathione peroxidase 4(GPX4)/Nrf2 and inhibition of nuclear receptor coactivator 4 (NCOA4) in diabetes. CCA exerted excellent antidiabetic effects via inhibition of ferroptosis, so it may be a promising agent for diabetes therapy, providing a new avenue for diabetes treatment.