The challenge of antimicrobial resistance impelled the search for therapeutic agents from medicinal plants. This study aimed at assessing the synergistic activity of Terminalia catappa leaf extract and ciprofloxacin against multidrug-resistant Escherichia coli. Fresh leaves were collected and then allowed to dry for weeks. They were ground and extracted by means of cold maceration using ethanol (ethyl acetate). The organisms were identified and characterized using appropriate methods. Antibiotic susceptibility testing of the organisms against different antibiotics was carried out. Preliminary antimicrobial assay for Terminalia cattapa and Ciprofloxacin was done using the agar diffusion method. The combination studies of Terminalia cattapa and Ciprofloxacin were carried out using a checkerboard assay. The results confirmed them as isolates of Escherichia coli. These isolates were multidrug resistant. Preliminary test results showed minimal activity of ciprofloxacin and the extract against the strains of Escherichia coli, with the extract seemingly showing more promise of activity. The combination study exhibited some levels of synergy and potentiation of individual effects. The results substantiate the medicinal claim of Terminalia catappa for the treatment of E. coli infections. This study is a modest attempt at discovering an advanced therapeutic option. Further studies are necessary to ascertain the active agents responsible for the observed activity, their safety, and the genetic basis of bioactive compounds.