Drug resistance remains a critical challenge in cancer chemotherapy, particularly in oral squamous cell carcinoma (OSCC). Recent findings have highlighted the significant roles that autophagy and extracellular vesicles (EVs) play in contributing to chemoresistance. In previous studies, we demonstrated that EVs are essential in mediating cisplatin resistance in human OSCC cells. In this study, we sought to investigate the involvement of autophagy-related proteins in cisplatin resistance and their potential as non-invasive predictive biomarkers to enhance OSCC treatment strategies. Using bioinformatics analyses, we identified key autophagy-related proteins that may play a role in cisplatin resistance in OSCC cells. We then employed cisplatin-sensitive and -resistant OSCC cell models to investigate further the involvement of autophagy and EVs in drug resistance. The expression of the identified autophagy-related proteins was analyzed in OSCC cells and their EVs to explore their correlation with cisplatin resistance. Our bioinformatics analyses identified ATG12 and LC3B as potentially significant contributors to cisplatin resistance. Both autophagy and EVs were found to promote drug resistance in our OSCC cell models. Furthermore, we observed a positive correlation between cisplatin resistance and the expression of ATG12 and LC3B proteins in OSCC cells. Notably, LC3B-II expression was elevated in EVs derived from cisplatin-sensitive cells, suggesting its potential role in mediating resistance via EVs in OSCC. Our findings underscore the potential of LC3B-II as a non-invasive predictive biomarker for cisplatin resistance in OSCC. These results may pave the way for improved therapeutic strategies targeting drug resistance mechanisms in OSCC.