Medicinal plants have been used for the maintenance of health for many years. Emerging cases of adverse drug reactions, high cost, and antimicrobial resistance using a single antimicrobial drug have heightened the need for research into plant sources of antimicrobial activity like Melia azedarach and Solanum incanum. This research investigated the synergistic antimicrobial activity exhibited by ethanolic leaf extracts obtained from Melia azedarach and Solanum incanum when tested against the pathogenic bacterium Escherichia coli. The study aimed to characterize the presence and composition of phytochemicals in the individual extracts, thereby elucidating their contribution to the observed antimicrobial effects. Additionally, minimum inhibitory concentration (MIC) assays and disc diffusion tests were performed to determine the optimal concentration required to inhibit the growth of Escherichia coli. Solanum incanum at a concentration of 2g/ml showed an average zone of inhibition of 6.92mm while Melia azedarach exhibited a zone of inhibition of 6.97 mm for Escherichia coli. The combined extracts showed a zone of inhibition of 8.34 mm for Escherichia coli. The minimum inhibitory concentration for Solanum incanum was 0.5g/ml while that of Melia azedarach was 1.4g/ml for Escherichia coli. Leaf extracts of both Melia azedarach and Solanum incanum had moderate to high levels of tannins, coumarins, flavonoids, and anthraquinones. Alkaloids and saponins were in low amounts in both extracts while steroidal glycosides were in moderate amounts in Melia azedarach but high in Solanum incanum. In conclusion, both plant extracts demonstrated significant antibacterial effects with both plants having a similar potency in terms of zone of inhibition diameter. The combined leaf extract of both plants had higher activity compared to individual plant extracts. We thus recommend that the combined extract can be used as an alternative modality for treating E. coli infections of mild severity without complications.