In the present study a series of 20 histone deacetylase 8 (HDAC8) inhibitors were used for generation of pharmacophore. A five features pharmacophore with one hydrogen bond acceptor (A), two hydrogen bond donors (DD) and two ring aromatics (RR) was developed and used for searching compound database. A statistically significant atom based 3D QSAR model was built by selecting best pharmacophore hypothesis ADDRR.3 with R2 = 0.9821 for training set of 14 molecules and Q2= 0.7314, RMSE= 0.1709, Person-R= 0.9061 for test set of 6 molecules. These parameters indicate that the model is a good predictive model. Docking study of known inhibitors as well as hits resulted after data base searching having fitness score ≥ 1 was performed. Docking analysis shows the important residues in the active site of receptor are Zn-388, TYR-306, HIS-142, PHE-152, PHE-208, GLY-151, and HIE-180. The XP glide score of highest active compound 1 and lowest active 20 are -11.73 and -6.036 respectively, which corroborated with experimental activity. On the basis of pharmacophore matching, predicted activity and docking interactions 5 novel chemical scaffold (Code No: CACPD2011a-0001275680, CACPD2011a-0000573705, CACPD2011a-0001843791, CACPD2011a-0000300107, CACPD2011a-0000291783) are reported as potent HDAC8 inhibitors.