Abstract: The growing threat of antimicrobial resistance requires the urgent development of new therapeutic strategies and agents. Bacteriophage therapy offers a promising alternative, utilizing phages' ability to specifically recognize and lyse bacterial cells. The ubiquity of bacteriophages subjects bacteria to constant evolutionary pressure, driving the emergence of diverse systems that defend against phage infection. The repertoire of phage defense genes includes a wide range of functions, such as nucleases, helicases, and ATPases. Host-phage interactions are complex and multifaceted. Bacterial defense mechanisms operate at various levels: initial innate defenses that inhibit phage adsorption, block nucleic acid injection, and interfere with virion assembly; early vesicle rupture targeting phage nucleic acids; systems that specifically target phage DNA and RNA; and abortive infection, which results in the degradation of bacterial nucleic acids, depletion of NAD⁺, and changes in cell membrane integrity. Notably, abortive infection prevents phage propagation, though at the cost of bacterial cell death. Although many defense systems have been predicted and identified through bioinformatics, the precise molecular mechanisms and detailed pathways of most systems remain poorly understood. Future research should focus on clarifying the exact molecular mechanisms, regulatory networks, distribution patterns, and roles in bacterial fitness for both newly discovered and established defense systems. Such insights are essential for developing innovative strategies to combat bacterial infections. This review examines the core mechanisms and application potential of bacterial antiphage defense. It systematically summarizes four key aspects of the bacterial antiphage defense system: early infection defense, phage nucleic acid-targeted defense, abortive infection defense, and transferable defense strategies. It also highlights current bottlenecks in the field, such as unclear defense mechanisms, insufficient clinical transformation technologies, and risks associated with the transferability of defense systems. Corresponding countermeasures and suggestions are proposed, including in-depth mechanistic research, construction of defense profiles for pathogenic bacteria, and development of engineered phages and synergistic therapies, to provide references for optimizing phage therapy and innovating bacterial infection treatment, thereby offering new perspectives for treating bacterial infections.