Pseudomonas aeruginosa is a significant opportunistic pathogen, particularly prevalent in intensive care units (ICUs). Through a comprehensive genomic and phenotypic analysis of 518 ICU and healthy isolates collected over a 13‐year period (2010–2022), we found that ICU strains, despite reduced sequence type (ST) diversity, are dominated by persistent high‐risk clones, notably ST463 and ST1076. Despite possessing a lower overall prophage content, ICU isolates show a broader and more diverse repertoire of anti‐phage defense systems. This strengthened defense capacity correlates with ICU strains, demonstrating heightened resistance to phage challenge and contributing to lower historical phage exposure. Concurrently, ICU isolates harbor a significantly higher antimicrobial resistance (AMR) gene burden. Our detailed genomic analysis shows that this increased AMR is primarily driven by plasmid acquisition. Importantly, AMR genes associated with prophage elements are exclusively found in ICU isolates, highlighting their selective retention and functional contribution to resistance in this high‐pressure environment. Furthermore, specific virulence genes, including exoU, pilA, and rhsP2, are more prevalent in ICU strains, indicating enhanced pathogenicity. Collectively, these findings underscore a qualitative distinction in ICU P. aeruginosa: their dominance and persistence stem from highly adapted clones, robust anti‐phage defenses, rapid plasmid‐mediated AMR acquisition, and clinically selected prophage‐borne AMR.