Abstract Background Cuproptosis is recently emerging as a hot spot in cancer research. However, its role in pancreatic adenocarcinoma (PAAD) has not yet been clarified. This study aimed to explore the prognostic and therapeutic implications of cuproptosis-related genes in PAAD. Methods Two hundred thirteen PAAD samples from the International Cancer Genome Consortium (ICGC) were split into training and validation sets in the ratio of 7:3. The Cox regression analyses generated a prognostic model using the ICGC cohort for training (n = 152) and validation (n = 61). The model was externally tested on the Gene Expression Omnibus (GEO) (n = 80) and The Cancer Genome Atlas (TCGA) datasets (n = 176). The clinical characteristics, molecular mechanisms, immune landscape, and treatment responses in model-defined subgroups were explored. The expression of an independent prognostic gene TSC22D2 was confirmed by public databases, real-time quantitative PCR (RT-qPCR), western blot (WB), and immunohistochemistry (IHC). Results A prognostic model was established based on three cuproptosis-related genes (TSC22D2, C6orf136, PRKDC). Patients were stratified into high- and low-risk groups using the risk score based on this model. PAAD patients in the high-risk group had a worse prognosis. The risk score was statistically significantly correlated with most clinicopathological characteristics. The risk score based on this model was an independent predictor of overall survival (OS) (HR = 10.7, p