Salmonella spp. and Escherichia coli (E. coli) O157:H7 are important food-borne pathogens. This study determined the antibiotic resistance and multiple antibiotic resistance (MAR) index of Salmonella spp. and E. coli O157:H7 isolated from smoked rat meat sold in Zaria, Nigeria. A total of 384 samples were obtained for this study. The samples were analyzed in the laboratory by conventional biochemical techniques, Microgen GN-ID A+B kit for gram negative bacteria, and Rapid latex agglutination kit for E. coli O157:H7. Confirmed isolates were further subjected to antimicrobial susceptibility testing by the Agar disc diffusion technique. Results showed that both Salmonella and E. coli O157:H7 isolates exhibited multidrug resistance. Of the total (6) Salmonella isolates, 100% were resistant to tetracycline (30µg), doxycycline (30µg), amoxicillin/clavulanic acid (30µg), trimethoprim/sulfamethoxazole (25µg) and ampicillin (10 µg), 83.3% resistant to chloramphenicol (30µg) and cefixime (5µg), 66.6% resistant to gentamicin (30µg), 33.3% resistant to azithromycin (15µg), 16.6% resistant to kanamycin (30µg) and cefuroxime sodium (30µg), with no isolate (0%) resistant to ciprofloxacin (5 µg). Of the total (5) E. coli O157:H7 isolates, 100% were found to be resistant to ampicillin (10 µg) and penicillin (10 i.u), 80% resistant to streptomycin (10 µg), 60% resistant to trimethoprim/sulfamethoxazole (25 µg) and doxycycline (30µg), 40% resistant to chloramphenicol (30µg) and gentamicin (30µg), with no isolate (0%) resistant to imipenem (30µg). All isolates had MAR index of >2. The multiple antimicrobial resistance exhibited by the Salmonella and E. coli O157:H7 strains in this study is an indication of possible antibiotic abuse. Therefore, indiscriminate use of antibiotics should be discouraged.