BACKGROUND: Uveal melanoma (UVM) is a rare yet aggressive form of ocular cancer with a poor prognosis. This study aims to investigate the role of oxidative stress-related genes (OSGs) in UVM, focusing on their involvement in key signaling pathways and immune infiltration and their potential as prognostic biomarkers and therapeutic targets. METHOD: Differential gene expression analysis was conducted using 175 samples of normal retinal pigmented epithelium-choroid complex samples and 63 samples from UVM. Protein-protein interaction (PPI) networks were constructed to identify hub genes, and machine learning algorithms were utilized to screen for diagnostic genes, employing methods such as least absolute shrinkage and selection operator (LASSO) regression, random forest, support vector machine (SVM), gradient boosting machine (GBM), neural network algorithm (NNET), and eXtreme gradient boosting (XGBoost). A risk signature model was developed using data from The Cancer Genome Atlas (TCGA) cohort and validated using the International Cancer Genome Consortium (ICGC), GSE84976 dataset. Clinical samples were used to validate the diagnostic value. Experimental validation encompassed HO-induced oxidative stress assays and CALM1 overexpression analysis in UVM cells to evaluate its protective effects. RESULTS: A total of 2,576 differentially expressed genes (DEGs) were identified, with 185 overlapping OSGs enriched in pathways such as HIF-1, FoxO, PI3K-Akt, and apoptosis. Prognostic hub OSGs, including ACACA, CALM1, and DNM2, were associated with poor survival outcomes in the training set and multiple validation data. Revalidation using clinically collected samples confirmed that CALM1 exhibits superior diagnostic value. The risk signature model demonstrated strong predictive accuracy for a 5-year overall survival (AUC = 0.844). Immune infiltration analysis revealed increased CD4 memory-activated T cells and mast resting cells in the high-risk group. Additionally, CALM1 overexpression attenuated HO-induced oxidative stress and apoptosis in UVM cells. CALM1 upregulation also mitigated the inhibitory effects of HO on key cellular processes, including proliferation, migration, and invasion. CONCLUSION: This study underscores the critical role of OSGs in the progression of UVM and their potential as prognostic biomarkers and therapeutic targets. The identified risk signature model and the protective role of CALM1 offer valuable insights for developing targeted therapies and enhancing patient clinical outcomes in UVM.