Malaria caused by Plasmodium affects millions people worldwide. Plasmodium consumes hemoglobin during its intraerythrocytic stage leaving toxic heme. Parasite detoxifies free heme through formation of hemozoin (β-hematin) pigment. Proteolysis of hemoglobin and formation of hemozoin are two main targets for antimalarial drugs. Quinoline anti-marital drugs and analogs were studied as inhibitors of β-hematin formation. A computer assisted methodology was applied for the construction of pharmacophore and for building 3D QSAR model of novel Isocryptolepine derivatives as a β-hematin Inhibitors. 3D QSAR model of Isocryptolepine derivative based on common featured pharmacophore was developed using BIOVIA Discovery Studio software. A series of 49 analogues of Isocryptolepine derivatives as anti-plasmodial activity against P. falciparum (IC50) was selected and used to develop the Pharmacophore based 3D QSAR model. The best pharmacophore model (Hypo1) exhibits all the important chemical features required for β-hematin inhibitors. The correlation coefficient, root mean square deviation (RMSD) and cost difference were 0.864099, 0.948278 1.0719 and 24.272, respectively, suggesting a good predictive ability of the model (Hypo1) among all the ten pharmacophore models that were analyzed.