<p>Multidrug-resistant <i>Pseudomonas aeruginosa</i> (MDR <i>P. aeruginosa</i>) has emerged as a major threat in contemporary clinical microbiology, driven by the convergence of extensive antimicrobial resistance, biofilm-mediated persistence, and tightly coordinated virulence regulation. Global surveillance reveals a sustained increase in MDR and carbapenem-resistant <i>P. aeruginosa</i> (CRPA), characterized by marked regional heterogeneity and the dissemination of high-risk international clones. Conventional antibiotic-centered strategies are increasingly compromised by the interplay between intrinsic resistance determinants, including low outer membrane permeability, multidrug efflux systems, and inducible β-lactamase, and acquired mechanisms such as carbapenemases, target-site mutations, and adaptive biofilm-associated tolerance. This review presents a systems-level framework that integrates global epidemiology, resistance architecture, clinical manifestations of acute and chronic infections, pathogenicity, diagnostic innovation, and emerging therapeutic strategies into a cohesive translational perspective. Emphasizing the mechanistic convergence of resistance, persistence, and virulence reframes MDR <i>P. aeruginosa</i> as a dynamically regulated pathogenic network rather than solely a drug-resistant organism. Next-generation interventions are critically examined within the context of precision diagnostics and antimicrobial stewardship. Taken together, these developments signal a shift from antibiotic escalation toward integrated, precision-informed, and evolution-aware therapeutic frameworks. Sustainable control of MDR <i>P. aeruginosa</i> will require coordinated implementation of targeted pathogen disruption, rapid molecular diagnostics, robust stewardship strategies, hygiene measures, and antimicrobial resistance surveillance to redefine antimicrobial practice as we get closer to the post-antibiotic era.</p>