This study was conducted to determine the antibiotic resistance profile of Escherichial Coli isolate from apparently healthy domestic livestock viz: cow, goats and chicken from Osun State Nigeria. E. Coli was isolated using Eosin methylene Blue Agar (EMB) and identified by conventional microbiological technique. The isolate were tested against 14 antibiotics using the disc diffusion method. A total of 42 different antibiotics resistance profile were observed with each isolate showing resistance to at least four or more drugs tested. Generally, the E. coli isolates showed resistance rates of 93.8% to Ampicilin; 15.3% to Chloramphenicol, 52.7% to cloxacillin, 74.3% Erythromycin, 20.9% to Gentamicin, 53.8% to Penicillin, 17.7% to Streptomycin, 67.3% to Tetracyclin, 21.1% to Ceftazidine 70.7% to Cefuroxine, 20.5% to Cefixine, 28.8% to Ofloxacine, 58.6% to Augmentin, 27.2% to Nitorfurantion 27.3% to Ciprofloxacin. Statistical analysis showed that average number of resistance phenotypes per isolate was significantly higher for cow compared with poultry. A significant public health concern observed in this study is that multi drug resistant: commensal E. Coli strains may constitute a potential reservoir of resistance genes that could be transferred to pathogenic bacteria.