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Pseudomonas aeruginosa is a priority multidrug-resistant pathogen causing significant healthcare-associated infections worldwide. Despite global surveillance data, comprehensive information on its antimicrobial resistance patterns in Belize remains limited, hindering evidence-based treatment and stewardship efforts. We conducted a nationwide retrospective analysis of P. aeruginosa isolates from clinical specimens (blood, pus, sputum, urine, and wound) recorded in the Belize Health Information System from January 2018 to December 2024. Data were aggregated at district-year level and analyzed using mixed-effects regression models to identify risk factors for multidrug resistance (MDR), defined as resistance to ≥3 antibiotic classes. Spatial autocorrelation was assessed using Moran's I statistic. Temporal trends were modeled using linear regression, and an Antibiotic Vulnerability Index was calculated to monitor effectiveness of key therapeutic agents. Among 1,271 isolates analyzed, the overall MDR prevalence increased from 28.3% in 2018 to 41.8% in 2024, representing an average annual increase of 2.3% (95% CI: 1.8-2.8%, p < 0.001). Significant spatial clustering was detected (Moran's I = 0.42, p = 0.018), with urban districts showing 2.32 times higher odds of MDR compared to rural areas (95% CI: 1.81-2.97, p < 0.001). The COVID-19 pandemic period was independently associated with 40% higher odds of MDR (OR = 1.40, 95% CI: 1.05-1.86, p = 0.021). The Antibiotic Vulnerability Index declined by 20% (from 71.8% to 57.8%) over the study period, indicating substantial erosion of effective treatment options. Multidrug-resistant P. aeruginosa represents a significant and escalating public health threat in Belize, with distinct spatial clustering in urban centers and concerning temporal acceleration. These findings underscore the urgent need for targeted antimicrobial stewardship programs, enhanced surveillance, and evidence-based treatment guidelines to mitigate resistance spread and preserve therapeutic options in Belizean healthcare settings. Multidrug-resistant Pseudomonas aeruginosa is increasing across Belize, with prevalence rising from 28% to 42% from 2018–2024. Urban districts show 2.3× higher resistance than rural areas, with significant spatial clustering around healthcare centers. The COVID-19 pandemic accelerated resistance trends by 40%. The Antibiotic Vulnerability Index declined by 20% (from 71.8% to 57.8%) over the study period, indicating substantial erosion of effective treatment options. These findings highlight an urgent need for targeted stewardship programs and evidence-based guidelines to combat antimicrobial resistance in Belize and preserve essential antibiotics for future use. • This first nationwide analysis of Pseudomonas aeruginosa in Belize demonstrates a concerning escalation in multidrug resistance from 28.3% in 2018 to 41.8% in 2024, with an average annual increase of 2.3%. • Significant spatial clustering was identified, with urban districts showing 2.32 times higher odds of multidrug resistance compared to rural areas, highlighting the need for targeted interventions in high-burden healthcare facilities. • The COVID-19 pandemic period was independently associated with 40% higher odds of multidrug resistance, and the Antibiotic Vulnerability Index declined by 19.4% over seven years, indicating substantial erosion of effective treatment options. • Projections based on current trends suggest that multidrug resistance rates could reach 50% by 2027, threatening to compromise empirical therapy for common infections in Belizean healthcare settings. • These findings from Belize carry important implications for Latin America, the Caribbean, and Small Island Developing States, where similar vulnerabilities, including limited laboratory capacity, tourism-related transmission risks, and concentrated urban healthcare infrastructure, may drive comparable resistance patterns.