Bladder cancer (BLCA) is one of the most common urological malignancies worldwide, including in Taiwan, where its incidence has been increasing. It accounts for approximately 3% of all newly diagnosed cancer cases. Drug resistance remains a major challenge in BLCA treatment, particularly at the metastatic stage, where only 35% of metastatic BLCA patients respond to cisplatin chemotherapy, and most eventually develop resistance. In the present study, we established cisplatin-resistant BLCA cell models (T24 and UMUC3) and analyzed ATP-binding cassette (ABC) transporters. We identified ABC transporter C member 6 (ABCC6) as a crucial transporter upregulated in cisplatin-resistant BLCA cells. Further analysis showed that ABCC6 knockdown affected autophagy-related markers, and inhibition of autophagy using bafilomycin A1 (BafA1) and chloroquine (CQ) reversed cisplatin resistance. These findings suggest that ABCC6 contributes to cisplatin resistance in BLCA through autophagy regulation. Our study highlights ABCC6 as a crucial factor in BLCA cisplatin resistance, with autophagy playing a significant role in this mechanism. Targeting autophagy may offer a potential strategy to overcome chemoresistance in BLCA. Future research should focus on validating these findings in clinical samples and exploring ABCC6 inhibitors or autophagy modulators as therapeutic options.