Extra-Intestinal Pathogenic Escherichia coli (ExPEC) is a predominant Gram-negative bacterial pathogen and is responsible of several diseases including Urinary Tract Infections (UTI), nosocomial pneumonia, and neonatal meningitis. ExPEC isolates are often multidrug resistant and clones producing Extended-Spectrum Beta-Lactamases (ESBL) are increasingly reported all over the world. Seventy-eight clinical ExPEC strains (49 Community-Acquired (CA) and 29 Hospital-Acquired (HA)) were selected for this study. The majority was from UTIs (n=51), while the rest (n=27) was from pus, sputum, bronchial fluid and vaginal samples (non-uropathogenic ExPEC). Antibiotic susceptibility testing was performed using the Kirby-Bauer disc diffusion method. Standard polymerase chain reaction was used to screen major ESBL genes (blaCTX-M, blaOXA-1, blaTEM, blaSHV) and blaCTX-M variants (blaCTX-M-1, blaCTX-M-9, blaCTX-M-15, blaCTX-M-25). All the tested isolates were resistant to ampicillin, ticarcillin, amoxicillin/ clavulanic acid combination, cefalotin, cefotaxime, ceftazidime, cefepime and aztreonam, but showed a high susceptibityto fosfomycin (98.7%, n = 77), ertapenem (96.2%, n = 75), and imipenem (100%). Moreover, isolates harbored at least one ESBL gene, including blaCTX-M (98.7%), blaOXA-1 (78.2%), blaTEM (44.9%) and blaSHV (3.8%). The CTX-M variants were also found with the predominance of blaCTX-M-1 (89.7%) and blaCTX-M-15 (89.7%) followed by blaCTX-M-9 (11.5%). Despite the resistance to most of the tested antibiotics, ExPEC isolates showed fortunately good susceptibility to fosfomycin and carbapenems. blaCTX-M1, blaCTX-M15 and blaOXA-1 seem to be E.coli major ESBL genes circulating in Senegal. The high level of resistance to antimicrobials observed stresses the need of establishing an epidemiological surveillance of antimicrobial resistance in both community and hospital settings.