Background Food-borne diseases related to the consumption of meat and its products had public health importance worldwide. The problem became worst in Ethiopia as the result of the tradition of eating raw cattle meat. Salmonella species and Escherichia coli are important food-borne pathogens associated with meat contamination. Hence the current study aimed to assess the prevalence and antimicrobial susceptibility of Salmonella species and Extended-spectrum β-lactamase producing Escherichia coli from raw cattle meat at butcher houses in Hawassa city, Sidama regional state, Ethiopia. Method A cross-sectional study was done on the prevalence and antimicrobial susceptibility pattern of Salmonella species and Extended-spectrum β-lactamase producing E.coli from raw cattle meat at butcher houses in Hawassa city from September to December 2020. Socio-demographic data were collected using a structured questionnaire and raw cattle meat and swab samples were collected from meat cutting equipment. The collected samples transported using icebox to Hawassa University College of Medicine and Health Sciences Microbiology Laboratory for identification. Samples were grown on different culture media and antimicrobial susceptibility tests were determined by using Kirby disc diffusion method. Data were entered and analyzed into SPSS version 23. Descriptive statistics were done and P-value < 0.05 was considered as statistically significant. Result The overall prevalence of salmonella and ESBL producing E.coli among 556 samples collected from 278 butcher houses was 36 (6.47%) (95% CI: 1.68–1.79) of which 13 (2.3%) were ESBL producing E.coli and 23(4.1%) were salmonella species. Poor hand washing practice (AOR = 2.208; 95% CI: 1.249–3.904) and touching birr while selling meat (AOR = 0.75; 95% CI: (0.433–1.299) were found to be significantly associated with the prevalence of salmonella species and E.coli on cattle meat. The isolates showed moderate levels of resistance (60–70%) against Amoxicillin/ clavulanic acid and high susceptibility (85–100%) against gentamicin, cotrimoxazole, ceftazidime, and tetracycline and the overall multidrug resistance was 33.3%. Conclusion This study revealed moderately high prevalence of salmonella and E.coli due to poor hygiene and sanitation practices in the butcher shops. Furthermore, the existence of ESBL producing E.coli isolates clearly indicate the possible threat to public health. Therefore, inspection by the right agencies must be implemented in order to prevent food-borne outbreaks and antimicrobial resistance.