The aim of this study is to determine the zones of inhibition, phytochemical screening and molecular docking (In-silico Approach) of Tithonia diversifolia (Hemsl.) A. Gray and Jatropha gossypiifolia L against selected clinical and multi drug resistant isolates. Crude extraction of air dried leaves were carried out by soaking the plant in ethanol and ethyl acetate, standard agar diffusion method was used for sensitivity testing, minimum inhibitory concentration and minimum bactericidal concentration values were obtained by agar dilution method. The antimicrobial activity of the leaf extracts of T. diversifolia (Hemsl.) A. Gray and J. gossypiifolia L was assayed against Bacillus subtilis, Escherichia coli, Klebsiella pneumonia, Proteus mirabilis, Pseudomonas aeruginosa, Salmonella typhi, Shigella dysentriae, Staphylococcus aureus, Streptococcus pyogenes, Candida albican and against multi drug resistant bacteria which are Acinetobacter baumannii, Enterobacter agglomerans, Proteus mirabilis, Providencia stuartii, Salmonella subsp 3b. Levofloxacin and fluconazole were the standard antibiotics used. Sensitivity test revealed the highest zone of inhibition observed for J. gossypiifolia L and T. diversifolia (Hemsl.) A. Gray against Candida albican with mean and standard deviation of 29±1.414 and 19.5±0.707 at 100 mg/ml respectively, while the least zone of inhibition was observed from the extracts of J. gossypiifolia L against Escherichia coli with 11.75±0.354 at 100 mg/ml. Both plant extracts showed antimicrobial activity against multi drug resistant isolates having zones of inhibition ranging from 0 to 15±1.414. The Minimum Inhibitory Concentration of the extracts ranges between 6.25 and 100 mg/ml as well as the Minimum Bactericidal Concentration. The qualitative and quantitative phytochemical analysis showed the presence of alkaloids, anthraquinone, cardiac glycosides, flavonoids, phlobotannins, reducing sugars saponins, steroids and tannins. Molecular docking of the phytochemicals of T. diversifolia (Hemsl.) A. Gray only was carried out using levofloxacin as template, which revealed the presence of compounds more effective in inhibiting DNA gyrase enzyme. Thus, the use of both plants as traditional medicine is justifiable and should be encouraged in the formulation and production of new antibiotics.