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The treatment of implant‐associated bacterial infections and biofilms is an urgent medical need and a grand challenge because biofilms protect bacteria from the immune system and harbor antibiotic‐tolerant persister cells. This need is addressed herein through an engineering of antibody‐drug conjugates (ADCs) that contain an anti‐neoplastic drug mitomycin C, which is also a potent antimicrobial against biofilms. The ADCs designed herein release the conjugated drug without cell entry, via a novel mechanism of drug release which likely involves an interaction of ADC with the thiols on the bacterial cell surface. ADCs targeted toward bacteria are superior by the afforded antimicrobial effects compared to the non‐specific counterpart, in suspension and within biofilms, in vitro, and in an implant‐associated murine osteomyelitis model in vivo. The results are important in developing ADC for a new area of application with a significant translational potential, and in addressing an urgent medical need of designing a treatment of bacterial biofilms. [ABSTRACT FROM AUTHOR]