The current epidemic of antibiotic resistant bacterial infections has fueled the demand for novel antibiotics exhibiting both antibacterial efficacy and anti-antibiotic resistance. This need has not been fully satisfied by the conventional “one target–one molecule” approach. Consequently, there has been rising interest in the development of multi-target antibiotics. Over the past two decades, 52% (14 out of 27) of the FDA approved antibiotics have demonstrated synergistic, multi-target mechanisms of action. Among these are three second-generation lipoglycopeptides, five new generation quinolones and six modernized β-lactams. This review focuses on the structure-activity relationship (SAR) analysis and the polypharmacological drug action of these antibiotics, to reveal how these multi-target antibiotics achieve the dual objectives of maximizing bactericidal efficacy and minimizing antibiotic resistance. The entrance of multi-target antibiotics into the FDA-approved regimens represents a milestone in the evolution of drug discovery as it has transcended from chemical library screening to rational drug design.