A pragmatic approach to the treatment of infectious diseases with multicausal agents and prevention of the development of resistant isolates is the combination of herbal remedies with the first-line antimicrobial agents to which most of them have become resistant. This study evaluated the interactions between the ethanolic bark extract of Ziziphus mucronata with known antimicrobial agents in vitro. In this study, the results showed that varied zones of inhibitions (ZME-chloramphenicol (17-42 mm), ZME-amoxicillin (17-35 mm), ZME-tetracycline (17-36 mm), ZME-ciprofloxacin (20-41 mm), ZME-nalidixic acid (17-34 mm), and ZME-kanamycin (17-38 mm)) were produced by the antibacterial combinations. At the highest combined concentrations, 12 isolates (ZME-ciprofloxacin) > 10 isolates (ZME-chloramphenicol) = (ZME-kanamycin) > 6 isolates (ZME-amoxicillin) = (ZME-nalidixic acid) and 5 isolates (ZME-tetracycline) were inhibited with zones of inhibition greater than 20 ± 1.0 mm. Although the agar diffusion assay suggested that the interactions between the ethanolic extract of Z. mucronata and the antibiotics were both synergistic and additive in nature, the fractional inhibitory concentration indices (FICI) showed that the interactions were synergistic (54.17%), additive (27.78%), indifferent (16.67%), and antagonistic (1.39%). While the fractional inhibitory concentration indices (FICIs) for synergism ranged between 0.00391 and 0.5, that of additivity ranged between 0.516 and 1.0, indifferences ranged between 1.062 and 3.0 and antagonistic interaction was 5.0. The synergistic effects implied that the antibacterial combinations would be more effective and useful in the treatment of multicausal and multidrug-resistant bacteria than a single monotherapy of either antibacterial agent.