Purpose: Platinum-based compound cisplatin is widely used in various tumors, whereas its usage against many types of cancer, including prostate, is limited because of poor targeting, dose-limiting toxicity, and acquired resistance. Caffeine (Cfn) is a purine alkaloid compound and is widely consumed. Until now, a growing body of data has shown that Cfn has anticancer properties and is suitable for use with conventional chemotherapeutics. Thus, there is a need to develop more effective therapeutic approaches. Herein, we assessed the possible synergistic effect of Cfn with cisplatin in prostate cancer cells. Materials and Methods: Cell proliferation was evaluated by WST-1 assay. Autophagy, ubiquitin-proteasome system, unfolded protein response, endoplasmic reticulum stress, apoptosis, epithelial-mesenchymal transition (EMT), and androgenic signal-related numerous protein levels were analyzed by immunoblotting. Nucleus formation and cell death-related alterations were examined by immunofluorescence microscopy. Colonial growth was evaluated with a colony formation assay. Results: We found that androgen-sensitive prostate adenocarcinoma LNCaP cells were more sensitive to Cfn than metastatic prostate cancer Du145 cells and healthy prostatic cells PNT1A. Cousage of cisplatin and Cfn exhibited an expanded anticancer effect by inducing eukaryotic initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP Homologous Protein (CHOP) signaling and negatively regulating autophagic flux. Moreover, Cfn displayed anticancer effects, and cotreatment with cisplatin gradually enhanced these properties. Furthermore, Cfn reduced the EMT and c-Myc expression. Also, androgenic signaling was strongly restricted by the cotreatment of Cfn and cisplatin. Conclusion: Our results suggest that combining the usage of cisplatin with Cfn treatment may offer an advanced therapeutic approach to prostate cancer.