Endometrial cancer (EC) represents one of the most prevalent malignancies of the female reproductive system. Ferroptosis, a recently identified form of programmed cell death, has garnered increasing attention in cancer research. Ubiquitin-specific peptidase 18 (USP18), a member of the deubiquitinating enzyme family, has been recognized as an oncoprotein in various cancers; however, its functional role and underlying mechanisms in EC remain largely unexplored. In this study, we found that USP18 was markedly upregulated in EC patients (n = 15, stage I; n = 4, stage II and n = 1, stage III), and elevated USP18 expression correlated with unfavorable prognosis. Functional assays demonstrated that knockdown of USP18 significantly inhibited EC cell proliferation. Moreover, USP18 silencing promoted the accumulation of lipid reactive oxygen species (ROS), malondialdehyde (MDA), and Fe