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This study investigated genomic differences in Australian and Indian <i>Pseudomonas aeruginosa</i> isolates from keratitis (infection of the cornea). Overall, the Indian isolates were resistant to more antibiotics, with some of those isolates being multi-drug resistant. Acquired genes were related to resistance to fluoroquinolones, aminoglycosides, beta-lactams, macrolides, sulphonamides, and tetracycline and were more frequent in Indian (96%) than in Australian (35%) isolates (<i>p</i> = 0.02). Indian isolates had large numbers of gene variations (median 50,006, IQR = 26,967–50,600) compared to Australian isolates (median 26,317, IQR = 25,681–33,780). There were a larger number of mutations in the <i>mutL</i> and <i>uvrD</i> genes associated with the mismatch repair (MMR) system in Indian isolates, which may result in strains losing their efficacy for DNA repair. The number of gene variations were greater in isolates carrying MMR system genes or <i>exoU</i>. In the phylogenetic division, the number of core genes were similar in both groups, but Indian isolates had larger numbers of pan genes (median 6518, IQR = 6040–6935). Clones related to three different sequence types—ST308, ST316, and ST491—were found among Indian isolates. Only one clone, ST233, containing two strains was present in Australian isolates. The most striking differences between Australian and Indian isolates were carriage of <i>exoU</i> (that encodes a cytolytic phospholipase) in Indian isolates and <i>exoS</i> (that encodes for GTPase activator activity) in Australian isolates, large number of acquired resistance genes, greater changes to MMR genes, and a larger pan genome as well as increased overall genetic variation in the Indian isolates.