Introduction: Diarrhea is one of the public health important diseases in developing countries. Among the causative agents of diarrhea, Salmonella serovars and Shigella species continue to play a major role in resource-limited countries. The aim of this study was to assess the prevalence of Salmonella and Shigella, risk factors, and antimicrobial susceptibility profiles among adult patients with complaints of diarrhea. Methods: A hospital-based cross-sectional study was conducted among adult patients with complaints of diarrhea at Hawassa University Comprehensive Specialized Hospital from March 2019 to November 2019. A structured questionnaire was used to collect sociodemographic, behavioral, and environmental characteristics of participants. Fecal samples were inoculated onto Selenite F broth and Xylose Lysine Dextrose media to isolate Salmonella serovars and Shigella species. Antibiotic susceptibility testing was performed by the Kirby-Bauer method. Data were analyzed by SPSS computer software version 20. Bivariate and multivariable analysis was used to determine the association between dependent and independent variables. Results: The overall prevalence of Salmonella serovars and Shigella species was 8.6% with 95% confidence interval (3.2–13.8). Participant those who do not wash their hands were three times more likely to be infected with Salmonella and Shigella ( p < 0.001) than their counterparts. Participants who consume uncooked food had about two times the chance to be infected with Salmonella and Shigella ( p < 0.001) than their counterparts. All serovars of Salmonella and serotypes of Shigella were resistant to ampicillin. Conclusion: In this study, relatively a high prevalence of Salmonella serovars and Shigella species was found among adult patients with complaints of diarrhea at Hawassa University Comprehensive Specialized Hospital. Consuming uncooked food and not washing hands were significantly associated with the prevalence of Salmonella and Shigella.