Antimicrobial resistance (AMR) is a critical global health threat, with a disproportionate burden on low- and middle-income countries where resistant infections occur at rates up to 60%, compared to 17% in high-income countries. Among multidrug-resistant (MDR) pathogens, Pseudomonas aeruginosa has emerged as a significant challenge, particularly in intensive care units (ICUs), where critically ill patients face heightened risks of infection due to invasive procedures, prolonged hospital stays, and extensive antibiotic use. This opportunistic Gram-negative pathogen causes severe infections, including respiratory tract infections, urinary tract infections, hospital-acquired pneumonia, and bacteremia, often resulting in treatment failures due to its intrinsic and acquired resistance mechanisms. The emergence of difficult-to-treat resistance (DTR) in P. aeruginosa is driven by diverse mechanisms, such as altered outer membrane permeability, efflux pump overexpression, antibiotic-inactivating enzymes, and biofilm formation. These mechanisms not only limit the efficacy of existing antimicrobial agents but also complicate therapeutic decision-making, especially for extensively drug-resistant (XDR) and pan-drug-resistant (PDR) strains. Recent advances in research highlight the potential of combining antibacterial agents with antibiofilm strategies to overcome these challenges, offering promising results in preclinical studies. This review examines the molecular underpinnings of DTR in P. aeruginosa, its clinical and epidemiological impact, and the innovative therapeutic approaches under development. By emphasizing the need for improved surveillance, targeted antimicrobial stewardship, and novel treatment strategies, this article underscores the urgent global effort required to combat the threat posed by DTR P. aeruginosa infections.