Extensive use of antibiotics for urinary tract infections has led to the emergence of drug-resistant microorganisms and one solution to this problem is to search for non-antibiotic compounds that exert anti-bacterial activity through different mechanisms such as non-steroidal anti-inflammatory drugs (NSAIDs). In this study, out of 100 urine samples; 48 Escherichia coli strains were detected, 47.9% were multi-drug resistant. The antibiogram resistance pattern of the strains was carried out by agar dilution method. Diclofenac sodium, indomethacin, aspirin and ibuprofen were tested against the E. coli isolates. Diclofenac sodium showed the lowest MIC 50 and MIC 90 ; 8 and 256 g/ml, respectively. Aspirin showed MIC 50 of 64 g/ml, while both indomethacin and ibuprofen showed MIC 50 of 256 g/ml. Indomethacin, aspirin and ibuprofen showed the same MIC 90 of 1024 g/ml. The combined effects of the four NSAIDs and five antibiotics (Amoxicillin, Augmentin, Cefotaxime, Ciprofloxacin and Gentamicin) were tested on five resistant clinical E. coli strains by checkerboard dilution technique. All the tested NSAIDs significantly reduced the minimum inhibitory concentrations (MICs) of antibiotics against the tested bacteria and fractional inhibitory concentration indices (FICIs) for this combination ranged from 0.03 to 0.5. In this study, leakage of intracellular components suggests that the effect of NSAIDs on E. coli could be the formation of pores in the plasma membrane and scanning electron microscopy (SEM) observations confirmed the damage to the structural integrity of the tested bacteria. In conclusion, NSAIDs showed antibacterial activity against E. coli causing urinary tract infections (UTIs), a combination of them and antibiotics exhibited good synergism and the mechanism of their action was by damaging the bacterial cell membrane.