The comparative molecular field analysis (CoMFA) based on three dimensional quantitative structure–activity relationship (3D-QSAR) studies were carried out employing, natural terpenes as potent antimycobacterial agents. The best prediction were obtained with a CoMFA standard model (q2 = 0.569, r2 = 0.999) using steric, electrostatic, hydrophobic and hydrogen bond donor fields. In the current study, a 3D QSAR model of natural product terpenes and their related derivative as antimycobacterial agents was developed. The resulted model exhibits wide-ranging in vitro potency towards Mycobacterium tuberculosis, with minimum inhibitory concentrations (MIC) from 0.25 μg/ml saringosterol through 200 µg/ml diaporthein A. In order to establish structure–activity relationships, 3D-QSAR studies were carried out using CoMFA for natural terpenes (secondary metabolite of plant origin products) as potent antitubercular agents. The in vitro Minimum Inhibitory Concentration (MIC) data against M. tuberculosis (Mtb) were used. The study was conducted using twenty four compounds. A QSAR model was developed using a training set of sixteen compounds and the predictive ability of the QSAR model was assessed employing a test set of eight compounds. The resulting contour maps produced by the best CoMFA models were used to identify the structural features relevant to the biological activity in this series of natural terpenes.