The spread of cefotaxime-resistant (CTX-R) Enterobacteriaceae in food animals constitutes a serious public health risk especially to humans in close proximity. We determined the point prevalence and antimicrobial resistance profile of CTX-R Enterobacteriaceae among food animals and in-contact humans in Southeast Nigeria. A total of 1,440 animals (cattle – 416, chicken – 296, goat – 287, pig – 283, sheep – 158) faecal and 406 human hand swab samples were randomly collected, enriched in peptone broth overnight and the Enterobacteriaceae were isolated on cefotaxime (5μg/ml) supplemented MacConkey agar. Antimicrobial susceptibility testing (AST) was performed on 430 randomly selected isolates from Abia (124), Ebonyi (170), and Enugu (145). The overall point prevalence of CTX-R Enterobacteriaceae in Southeast Nigeria was 84% (1549/1846) while the rates ranged between 76 ± 2.0% (95% CI 72 – 80%) to 88 ± 1.8 % (95% CI 84 – 91%) among the five states. All the 430 isolates subjected to AST were resistant to cefotaxime, ampicillin, and aztreonam while 91%, 80%, 76%, and 66% were resistant to ceftazidime, sulfamethoxazole /trimethoprim, tetracycline, and streptomycin respectively. Less than 40% of the isolates were resistant to amoxicillin/clavulanic acid, ciprofloxacin, gentamicin, norfloxacin, enrofloxacin, meropenem, and ofloxacin. The predominant resistance pattern in this study was ceftazidime-cefotaxime-aztreonam-ampicillin-streptomycin sulfamethoxazole/trimethoprim-tetracycline. The resistances observed among the isolates varied between abattoir, animal market and farms isolates. However, over 96% of the isolates had a multiple antibiotic resistance index (MARI) greater than 0.2, indicating a high-risk source of contamination.