Drug discovery is a lengthy and costly process which aims at bringing in a novel therapeutic molecule for the treatment of various diseases. In the present study, a novel series of eighty chalcone derivatives [(4-substituted)- (4'-substituted)-3' substituted sulphonyl (2E)- 1,3-diphenylprop-2-en-1-one] were designed to inhibit soluble epoxide hydrolase enzyme (sEH). Lipinski's rule of 5 and absorption, distribution, metabolism, elimination and toxicity (ADMET) properties of the compounds were calculated using Molinspiration server and Accord for excel software respectively. All 80 compounds have passed the Lipinski's rule of 5 and only 20 compounds showed considerable ADMET properties. These 20 compounds were subjected to molecular docking studies using AutoDock 4.2 in order to rationalize the possible interactions between test compounds and the active site of human soluble epoxide hydrolase enzyme (1ZD3). Binding energy, intermolecular energy and inhibition constant were the main parameters taken into consideration in this study. The binding energies ranged from -6.07 to -7.89 kcal/mol, the inhibition constant ranging from 1.64 μΜ to 35.45 μΜ and intermolecular energy ranging between -9.38 kcal/mol to -6.97 kcal/mol. Hence, further pharmacophore optimization and in vivo studies are necessary to develop potent chemical entities that could inhibit the sEH enzyme.