Background Salmonellas enterica serovar Typhi (S.typhi) causes typhoid fever and is a global health problem, especially in developing countries like Ethiopia. But there is a little information about prevalence and factors association with S.typhi and its antimicrobial susceptibility pattern in Ethiopia especially in the study area. The aim of this study was to determine the prevalence of S.typhi infection, its associated factors and antimicrobial susceptibility pattern among patient with a febrile illness at Adare General Hospital, Hawassa, Southern Ethiopia. Methods Hospital based cross sectional study was conducted among 422 febrile patients from May 23, 2018 to October 20, 2018. A 5 ml venous blood was collected from each febrile patient. Culture and biochemical test were performed for each isolate. Antimicrobial susceptibility testing was performed for each isolate using modified Kirby-Bauer disk diffusion techniques. Result In this study, the prevalence of S.typhi among febrile illness patients at Adare General Hospital was 1.6% [95% confidence interval (CI): 0.5–2.9]. The age of the study subjects were ranged from 15 to 65 years (mean age 32 years). It was observed that participants who came from rural area had 8 times (AOR 8.27: 95% CI: 1.33, 51.55) more likely to had S. typhi infection when compared with urban dwellers. The microbial susceptibility testing revealed that all six of S.typhi isolates showed sensitive to Ceftriaxone and all 6 isolates showed resistant to nalidixic acid and Cefotaxime and 5(83.3%) susceptible to Chloramphenicol and Ciprofloxaciline. Multidrug resistance (resistance to three or more antibiotics) was observed among most of the isolates. Conclusion S. typhi bacteraemia is an uncommon but important cause of febrile illness in our study population. Ceftriaxone therapy is a suitable empirical antibiotic for those that are unwell and suspected of having this illness. Further surveillance is required to monitor possible hanging antibiotic resistant patterns in Ethiopia.