Forty ethnobotanically selected phytocompounds and four conventional TB treatment drugs were screened for their in vitro inhibitory activity against two strains of Mycobacterium tuberculosis. Compounds with better minimum inhibitory concentrations (MICs), than that of any of the four conventional TB treatment drugs, were identified as promising leads. The study identified six promising leads; three benzoquinones (114, 121, and 116), a flavone (141), an isoflavone (145), and an alkaloid (151). Structure–activity relationships (SARs) and quantitative structure–activity relationships (QSARs) were generated for the flavonoid and the benzoquinone series members. QSARs were used in the prediction of structural modifications necessary for activity improvement and in the prediction of activity of untested compounds.