The aim of this study is to see the frequency, clinical presentation, and therapeutic response of extensively drug-resistant Salmonella enterica serovar Typhi and current susceptibility pattern of typhoidal Salmonella strains in our setup. This study was carried out at the Department of Medical Microbiology and Immunology and Department of Medicine, Pakistan Navy Ship (PNS) Shifa Hospital, Karachi, from January 1 to December 31, 2018. All the blood culture samples of patients (indoor and outdoor) with suspicion of enteric fever were processed. Isolates were cultured and identified using standard microbiological procedures. The antimicrobial sensitivity against the typhoidal Salmonellae was determined using Kirby-Bauer disc diffusion method as per the guidelines of Clinical and Laboratory Standards Institute (2018) and all the extensively drug-resistant (XDR) isolates were confirmed by Vitek 2 system. Clinical presentation and response to treatment of patients were followed. A total of 292 typhoidal Salmonella isolates were cultured. Resistance to ciprofloxacin against both Salmonella Typhi and Salmonella Paratyphi A was found to be very high (91%). Percentage of multidrug-resistant (MDR) isolates in Salmonella Typhi was 76% (182 isolates) and in Salmonella Paratyphi it was 34% (18 isolates). XDR isolates in Salmonella Typhi were significant that is 48% (115 isolates). Only 10 cases were given azithromycin who responded to treatment in mean 4.3 days. Out of 115 cases of XDR Salmonella Typhi, 103 patients were given parenteral meropenem and clinical response was seen in mean 5 days. The emergence and rapid spread of extensively drug-resistant Salmonella Typhi is alarming and highlights the significance of strict antimicrobial susceptibility surveillance programs with antimicrobial stewardship.