Objective: The aims of this study were to evaluate the antimicrobial activity and the genotoxic effect of both ethanolic and aqueous extracts of stem and leaf of Capparis spinosa (C. spinosa) plant on Escherichia coli (E. coli) ATCC 25922, Staphylococcus aureus (S. aureus) ATCC 6538P, clinical isolate of Methicillin-resistant S. aureus (MRSA) and Klebsiella pneumoniae (K. pneumoniae) and Candida albicans (C. albicans) ATCC 90028. Materials and Methods: The antimicrobial activity was determined using microbroth dilution method, while the genotoxic effect was investigated using randomly amplified polymorphic DNA (RAPD)-PCR and enterobacterial repetitive intergenic consensus (ERIC)-PCR. Results: The MIC values of both ethanolic and aqueous leaf and stem extracts of C. spinosa plant had a range 6.25 mg/ml to 100 mg/ml. In addition, it was found that ethanolic extract more effective than aqueous extract. The genotoxic activity of aqueous leaf extract, showed changes in both Random Amplified Polymorphic DNA (RAPD)-PCR and Enterobacterial Repetitive Intergenic Consensus (ERIC)-PCR profiles of E. coli strain treated with extract compared to untreated (negative) control. These changes included an alteration in the intensity, absence or appearance of new amplified fragments.Conclusions: Results of this study strongly show the genotoxic effect of aqueous leaf extract from C. spinosa plant on E. coli. The findings draw awareness to the possible toxic effect use of C. spinosa plant in traditional medicine and point out the capability of using C. spinosa to treat bacterial or fungal infections. More studies are needed to detect the exact ingredients of this plant as well as the mechanisms responsible for genotoxicity. Further in vivo genotoxicity studies are recommended to ensure and to evaluate the safety of using plants for therapeutic purposes. In addition, results of this study showed that molecular fingerprinting based on ERIC-PCR can be used to evaluate the genotoxic effect in the model bacterial species E. coli.