<p>There is a global rise of multidrug resistant (MDR) bacterial strains because of the use, misuse, and overuse of antibiotics, which is further causing major challenges in treating infections in clinical settings. Since 2000, only a few new antibiotics have been approved, and some of them have already been undermined because of the emergence of resistant bacteria. Pathogen-specific antibodies have the potential to serve as an alternative to antibiotics. These antibodies can bind to targets that are specific to the invading pathogens. Nonetheless, current advances in antibody engineering and molecular biology have allowed the generation of homogenous, defined, fully human and/or humanized monoclonal antibodies (mAbs) with a single antigen-specificity to target pathogens. Furthermore, the generation of mAbs only needs an antigen and an immunized or immune individual or an immunization platform. The emergence of MDR bacteria has greatly decreased the effectiveness of currently available antimicrobials, which has motivated the development of next-generation vaccines that are carefully designed to fight antibiotic resistance. Unlike traditional vaccines, vaccine platforms like recombinant protein, mRNA, and DNA vaccines are more innovative and effective in combating MDR-associated infections. In this review, the roles of both mAbs and next-generation vaccines against antibiotic-resistant infections, their mechanisms, preclinical and clinical trial-associated findings, and the advantages of using next-generation vaccines over traditional vaccines have been discussed. Moreover, the use of innovative tools like immunoinformatics and reverse vaccinology in developing next-generation vaccines against MDR bacteria has also been discussed in this review.</p>