Salmonella species and Escherichia coli (E.coli) are important foodborne pathogens affecting humans and animals. They are among the most important causes of infection that are associated with the consumption of contaminated food. This study aimed to determine the prevalence, antimicrobial susceptibility patterns, and associated risk factors for Salmonella species and E. coli in raw meat from butchery houses in Mekelle, Northern Ethiopia. Demographic data and risk factors were collected using a predesigned questionnaire. Meat samples were collected aseptically from the butchery houses and transported using an icebox to Mekelle University, College of Veterinary Sciences for the isolation and identification of Salmonella species and E. coli. Antimicrobial susceptibility patterns were determined using the Kirby disc diffusion method. Data obtained were cleaned and entered into Statistical Package for the Social Sciences version 22 and logistic regression models with odds ratio were calculated. P-value <0.05 was considered as statistically significant. A total of 153 out of 384 (39.8%) of the meat specimens were found to be contaminated. The contamination of Salmonella species and E.coli were 15.6% (n=60) and 20.8%) (n=80), respectively. Mixed contamination (Salmonella species and E.coli) was observed in 13 (3.4%) of the analyzed. Poor washing hands regularly (AOR=8.37; 95% CI: 2.75-25.50) and not using gloves during meat handling (AOR=11. 28; 95% CI: (4.69 27.10) were associated with an overall bacterial contamination. About 100% of the tested isolates were sensitive to Ciprofloxacin, gentamicin, Co trimoxazole (Trimethoprim-Sulphamethoxazole),sulfisoxazole/Sulphamethoxazole, ceftriaxone, and trimethoprim and ciprofloxacin, gentamicin and norfloxacine of E. coli and Salmonella species, respectively while the resistance of amoxyclav_ amoxicillin (clavulanic acid) and erythromycin were both isolated bacteria species. The overall multidrug resistance pattern for Salmonella and E. coli was 51.4% (n=19) and 31.8% (14), respectively. Of the 153 (153/384) contaminated raw meat, 60 (15.6%) and 80 (20.8%) were contaminated by Salmonella species and E. coli, respectively. Poor handwashing practices and not using gloves during meat handling showed significant association with bacterial contamination. Multidrug-resistant showed in Salmonella species and E. coli were 19 (51.4%) and 14 (31.8%), respectively.