Background: Pseudomonas aeruginosa is an opportunistic pathogen with both intrinsic and acquired antimicrobial resistance. High-risk clones are associated with carbapenem resistance because they frequently harbour and disseminate carbapenemase genes and other resistance determinants, enabling their persistence and spread in healthcare settings. Carbapenem-resistant strains have limited treatment options. However, genomic data on high-risk clones circulating in Ghana remain limited. Methods: This cross-sectional study was conducted between December 2023 and January 2024 in eight government hospitals in Accra, Ghana. Clinical isolates were collected from multiple specimen types and identified using standard antimicrobial susceptibility testing in accordance with CLSI guidelines to determine resistance profiles, and subsequently confirmed by MALDI-TOF-MS, Whole-genome sequencing was carried out using the Illumina NextSeq 2000 platform. Bioinformatic analyses were then conducted to determine sequence types, identify antimicrobial resistance genes and virulence factors, and assess phylogenetic relationships among the isolates. Results: High-risk international clones (ST235, ST244, ST308, and ST773) predominated. Low SNP differences (≤10 SNPs) indicated recent clonal transmission within and between hospitals. Serotype O11 was dominant and strongly associated with high-risk clones. Isolates carried multiple resistance determinants, including aminoglycoside-modifying enzymes and ESBL genes (blaCTX-M-15, blaTEM-1B) — carbapenemase genes, particularly blaNDM-1, coexisted with blaOXA-50 variants. Findings demonstrate local clonal expansion, global relatedness, and the emergence of a novel sequence type (ST5336) in Ghana. Conclusion: High-risk clones, especially ST773, are widely circulating in hospitals across Accra, indicating ongoing transmission and clonal expansion. The emergence of the novel ST5336, emphasize the urgent need for enhanced genomic surveillance and antimicrobial stewardship in Ghana. Significance of this research article: This work strengthens the evidence base needed to inform infection prevention strategies, antimicrobial stewardship programs, and the implementation of routine genomic surveillance to curb the spread of high-risk, carbapenem-resistant clones in Ghana and similar resource-limited settings.