In this study, we identified the protein disulfide isomerase (PDI) enzymes PDIA1 and PDIA5 as critical mediators of prostate cancer cell growth and survival. Our research demonstrated that these enzymes have a multifaceted role in prostate cancer: they protect cells from oxidative stress, maintain mitochondrial function, and have important functions as regulators of androgen receptor (AR), a critical oncogenic driver. Indeed, targeting PDIA1/PDIA5 causes destabilization of AR protein, and combining PDI inhibitors with AR-targeting drugs boosted antitumor responses. This work positions PDIA1/PDIA5 as viable therapeutic targets.