This review focuses on the mechanisms of antibiotic resistance in elderly patients, highlighting how aging-related factors such as immunosenescence, frailty, and multimorbidity increase the burden of infections from multidrug-resistant organisms (MDROs). It discusses novel strategies to mitigate resistance, including the development of next-generation antibiotics like teixobactin and cefiderocol, innovative therapies such as bacteriophage therapy and antivirulence treatments, and the implementation of antimicrobial stewardship programs. Advanced molecular diagnostic techniques, including nucleic acid amplification tests and next-generation sequencing, are also emphasized for their role in faster and more precise identification of resistant pathogens. Vaccine development, particularly through multi-epitope vaccines and nanoparticle-based platforms, is explored as a promising approach to prevent MDRO infections in the elderly. The role of machine learning (ML) in predicting resistance patterns and aiding in vaccine and antibiotic development is also discussed, offering personalized treatment and prevention strategies. By integrating cutting-edge diagnostics, therapeutic innovations, and ML-based approaches, the review underscores the importance of multidisciplinary efforts to address the global challenge of antibiotic resistance in aging populations.This review focuses on the mechanisms of antibiotic resistance in elderly patients, highlighting how aging-related factors such as immunosenescence, frailty, and multimorbidity increase the burden of infections from multidrug-resistant organisms (MDROs). It discusses novel strategies to mitigate resistance, including the development of next-generation antibiotics like teixobactin and cefiderocol, innovative therapies such as bacteriophage therapy and antivirulence treatments, and the implementation of antimicrobial stewardship programs. Advanced molecular diagnostic techniques, including nucleic acid amplification tests and next-generation sequencing, are also emphasized for their role in faster and more precise identification of resistant pathogens. Vaccine development, particularly through multi-epitope vaccines and nanoparticle-based platforms, is explored as a promising approach to prevent MDRO infections in the elderly. The role of machine learning (ML) in predicting resistance patterns and aiding in vaccine and antibiotic development is also discussed, offering personalized treatment and prevention strategies. By integrating cutting-edge diagnostics, therapeutic innovations, and ML-based approaches, the review underscores the importance of multidisciplinary efforts to address the global challenge of antibiotic resistance in aging populations.