Objectives: To highlight the importance of molecular testing in characterizing extensively drug-resistant (XDR) Salmonella Typhi (S. Typhi), and linking it to the current outbreak in Sindh, Pakistan. Methods: Our study reports three travel-related typhoid fever cases caused by XDR S. Typhi that presented between January 2019 and August 2019. Antimicrobial susceptibility and genotyping with pulse-field gel electrophoresis (PFGE) were carried out. Whole-genome sequencing (WGS) was performed to characterize the genomic clonality in relation to the emerging outbreak of S. Typhi in Sindh, Pakistan, and to study the molecular resistance profiles. Results: Laboratory testing revealed resistance to all first-line antibiotics (i.e ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole), as well as to quinolones and third-generation cephalosporins, leading to a change in the patients’ therapy to the use of carbapenems. Classical MLST (cMLST) revealed that the strains were of sequence type 1 (ST1) and the core genome sequence (cgWGS) analysis closely clustered our strains with internationally reported strains from Pakistan, India, and the UK. The strains were found to carry a blaCTX-15 gene-harbouring IncY plasmid, which encodes resistance to ceftriaxone. Conclusions: Our report alerts clinicians to the use of appropriate empirical treatments in such scenarios, and highlights the significance of the global spread of XDR S. Typhi.