Antimicrobial resistance (AMR) poses a significant global health challenge, necessitating advanced predictive models to support clinical decision-making. In this study, we explore multi-label classification as a novel approach to predict antibiotic resistance across four clinically relevant bacteria: E. coli, S. aureus, K. pneumoniae, and P. aeruginosa. Using multiple datasets from the DRIAMS repository, we evaluated the performance of four algorithms – Multi-Layer Perceptron, Support Vector Classifier, Random Forest, and Extreme Gradient Boosting – under both single-label and multi-label frameworks. Our results demonstrate that the multi-label approach delivers competitive performance compared to traditional single-label models, with no statistically significant differences in most cases. The multi-label framework naturally captures the complex, interconnected nature of AMR data, reflecting real-world scenarios more accurately. We further validated the models on external datasets (DRIAMS B and C), confirming their generalizability and robustness. Additionally, we investigated the impact of oversampling techniques and provided a reproducible methodology for handling MALDI-TOF data, ensuring scalability for future studies. These findings underscore the potential of multi-label classification to enhance predictive accuracy in AMR research, offering valuable insights for developing diagnostic tools and guiding clinical interventions.