The rise of antibiotic resistance has transformed once-curable infections into urgent global health threats, leaving hospitals with outbreaks, patients with prolonged illnesses, and doctors with limited therapeutic options. The era of antibiotic resistance is no longer a distant concern; it is a pressing reality demanding innovative solutions. Among emerging alternatives, cold plasma a partially ionized state of matter enriched with reactive species offers a multi-targeted antimicrobial strategy. Unlike conventional antibiotics, cold plasma disrupts bacterial survival through diverse mechanisms, including membrane rupture, protein and nucleic acid damage, and oxidative stress that overwhelms microbial defenses. This review synthesizes current evidence on the mechanisms of cold plasma, the factors influencing its antimicrobial efficacy, and its applications across healthcare, food safety, and environmental protection. In addition, it highlights the synergistic potential of cold plasma when combined with antibiotics, nanomaterials, or bacteriophages to enhance effectiveness against resistant pathogens. While challenges remain regarding safety validation, standardization, and large-scale application, cold plasma represents a promising non-traditional approach to complement existing therapies. This review not only summarizes recent progress but also outlines future directions, emphasizing its potential role in combating antibiotic resistance.