Pseudomonas aeruginosa is a significant pathogen mainly causing healthcare-associated infections (HAIs). Newly emerging high-risk clones of P. aeruginosa with elevated virulence profiles furtherly cause severe community-acquired infections (CAIs). Usually, it is not common for P. aeruginosa to co-carry exoU and exoS genes, encoding two type Ⅲ secretion system (T3SS) effectors. The pathogenicity mechanism of exoS⁺/exoU⁺ strains of P. aeruginosa remains unclear. Here, we provide detailed evidence for a subset of hypervirulent P. aeruginosa strains, which abundantly co-express and secrete the T3SS effectors ExoS and ExoU. The exoS⁺/exoU⁺ P. aeruginosa strains were available to cause both HAIs and CAIs. The CAI-associated strains could elicit severe inflammation and hemorrhage, leading to higher death rates in a murine acute pneumonia model, and had great virulence potential in establishing chronic infections, demonstrating hypervirulence when compared to PAO1 (exoS⁺/exoU) and PA14 (exoS^-/exoU⁺). Both ExoS and ExoU were co-expressed and co-secreted in abundance in exoS⁺/exoU⁺ strains. Their abundant protein secretion could boost exoS⁺/exoU⁺ strains’ potentials for cytotoxicity in vitro and pathogenicity in vivo. Genomic evidence indicates that exoU acquisition is likely mediated by horizontal gene transfer (HGT) of the pathogenicity island PAPI-2, while deletion of exoU was sufficient to mitigate virulence in the exoS⁺/exoU⁺ strains. Furthermore, bioinformatics analysis showed that such exoS⁺/exoU⁺ P. aeruginosa strains turned out to be widely distributed across the globe. Overall, the research provide detailed evidence for the high virulence and epidemicity of exoS⁺/exoU⁺ strains of P. aeruginosa, highlighting an urgent need for surveillance against these high-risk hypervirulent strains.