Background: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) poses a global health risk, yet there is insufficient knowledge about its sources and transmission routes within an integrated One Health framework. This study aimed to investigate CRPA presence and dynamics at the human-water interface inside and outside hospitals in three major cities located in different climatic zones. Methods: This cross-sectional study was conducted in Rotterdam (The Netherlands), Rome (Italy), and Jakarta (Indonesia) between March 2022 and June 2024. Samples were collected from humans, hospital environments, and various water sources. CRPA isolates underwent sequencing to determine carbapenemase gene presence and their genetic relatedness. Primary outcomes included CRPA carriage in healthy individuals and newly hospitalized patients, CRPA prevalence in hospital environments, CRPA concentrations in aquatic environments, and the frequency and transmission likelihood within epidemiological clusters. Findings: CRPA carriage was detected in 0·5% (1/194) of healthy individuals from Rotterdam, 0·0% (0/245) from Rome, and 0·8% (2/250) from Jakarta. Among patients, CRPA carriage differed significantly across cities (P<0·001), with 0·4% (2/469) in Rotterdam, 0·3% (1/363) in Rome, and 4·8% (28/584) in Jakarta. In wet hospital environments, CRPA prevalence ranged between 0·0% (Rome) and 13·4% (Jakarta). CRPA concentrations were highest in hospital wastewater and remained detectable in treated effluent of municipal wastewater treatment plants (mWWTP) and the receiving river in all cities. Carbapenemase genes were detected in 25·9% (100/386) of isolates. CRPA isolates identified in the clinical setting clustered with those from mWWTP influent or effluent (Rotterdam) or the river (Jakarta). High genetic diversity, overall and within reservoirs, was observed among isolates. Interpretation: The substantial presence of CRPA in environmental reservoirs, along with the cross-over between them, may pose a public health risk, and warrant mitigation strategies. To prevent CRPA transmission within hospitals and limit cross-sectoral transmission, robust infection prevention and control measures, alongside effective wastewater treatment, are essential.