Aim: The current study was aimed at evaluating the antibiotic resistance profile of Escherichia coli and Klebsiella spp isolated from post-weaned piglets treated with penicillin-streptomycin combination therapy. Study Design:  Bacteriological study. Place and Duration of Study: Laboratory of the National Reference Center for antibiotics at Institut Pasteur Côte d’Ivoire, between March 2018 and June 2018. Methodology: Escherichia coli and Klebsiella species were isolated from post weaned piglets stool on Mac Conkey medium added up separately with penicillin, streptomycin and combined penicillin-streptomycin and identified. Antibiotic susceptibility test was performed using disk diffusion method on Müller-Hinton agar. Results: Escherichia coli and Klebsiella species resistance to penicillin, streptomycin and combined penicillin-streptomycin evaluated, respectively, reached 80.5% (Day 0) to 92.0% (Day 4); 17.0% (Day 0) to 39.9% (Day 4) and 31.3% (Day 0) to 70.9% (Day 4) for piglets treated with Penstrep®. In addition, antibiotic susceptibility test carried out for Escherichia coli and Klebsiella spp strains isolated from piglets treated with Penstrep® revealed resistance to amoxicillin for each bacterial species at a rate of 86.0% and 89.0%. Furthermore, control piglets showed lesser resistance to streptomycin (E.coli 31.0% and Klebsiella spp 38.0%) than those treated with the combination therapy Penstrep® (E. coli 73.0% and Klebsiella spp 48.0%). As for netilmicin, imipenem and colistin, no resistance was detected for treated piglets as well as untreated ones. Conclusion: The combination therapy with Penstrep® has increased Escherichia coli and Klebsiella species resistance to antibiotics tested in the current study.