3D-QSAR studies were carried out on a training set of 53 structurally highly diverse analogues of triclosan to investigate the correlation of the structural properties of triclosan derivatives with the inhibition of the activity of enoyl acyl carrier protein reductase in Plasmodium falciparum (PfENR) by employing Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). The crystal structure bound conformation of triclosan, was used as a template for aligning molecules. The probable binding mode conformations of other inhibitors were explored according to molecular docking and molecular mechanics poisson-boltzmann surface area (MM/PBSA) solvation free energy estimation methods using grid based linear Poisson-Boltzmann calculations. Predictive 3D-QSAR models, established using routine database alignment rule based on crystallographic-bound conformation of template molecule, produced statistically significant results with cross-validated r2cv values of 0.64 and 0.54 and non-cross-validated r2ncv values of 0.96 and 0.97 for CoMFA and CoMSIA models, respectively. The statistically significant models were validated by a test set of nine compounds with predictive r2 values of 0.534 and 0.765 for CoMFA and CoMSIA respectively. Our QSAR model is able to successfully explain the geometric and electrostatic complementarities between ligands and receptor and provides useful guidelines to design novel triclosan derivatives as Plasmodium falciparum enoyl acyl carrier reductase inhibitors.