The quantitative structure–activity relationships of Plasmodium falciparum and Rat protein farnesyltransferase (PFT) inhibitory activities of 6-cyano-1-(3-methyl-3 H-imidazoly-4-ylmethyl)-3-substituted-1,2,3,4-tetrahydroquinoline (THQ) analogues are investigated in order to explore the similarities/deviations between the two enzymes for these analogues. The structure space of a ligand (BMS-214662) bound to Rat–PFT (PDB code 1SA5) has been used as the conformational space of the compounds under investigation. The study has been carried out using the combinatorial protocol in multiple linear regression with several 2D- and 3D-descriptors from molecular operating environment (MOE) representing the physicochemical and electronic features of the compounds. The molecular potential energy and partially charged van der Waals surface areas have taken part in the PFT models. They suggested in favor of molecular arrangement with minimum energy and low positively/negatively charged surfaces for optimum Pf–PFT inhibitory activity. Furthermore, less hydrophobic compounds are preferred for the activity. The Rat–PFT inhibitory activity models suggested in favor of more negatively as well as more positively charged surface area descriptors for the better activity. The PLS analysis carried out on the descriptors of the Pf–PFT and Rat–PFT models suggested that among the parameters, the partially charged surface areas in the range −0.20 to −0.15 (PEOE_VSA−3) and −0.30 to −0.25 (PEOE_VSA−5), hydrophobicity (a_hyd, log P(o/w) and S log P_VSA4), and electronic energy (PM3_Eele) of the molecules hold promise for modulating the Pf–PFT/R–PFT inhibitory activities of the compounds. This suggested the possibility of modulating the Pf–PFT/R–PFT inhibitory activities and bringing about selectivity in the THQ analogues for the malarial parasite enzyme.