Hispolon (H) is a natural phenolic type of bioactive compound with diverse biological activities. The analgesic action of hispolon is due to the inhibition of prostaglandins biosynthesis. However, the molecular basis of this inhibition has not been explored. Therefore, we have performed theoretical investigations to evaluate the molecular basis of analgesic action of hispolon by docking with cyclooxygenase 2 (COX-2). Further, we have conducted high throughput in silico screening of a compound library consisting of 1699 compounds to get novel COX-2 inhibitors with better pharmacokinetic and analgesic properties. The docking study was conducted on AutoDock vina in PyRx 0.8 and the drug-like properties were calculated by MarvinSketch 15.6.29. Further, the pharmacokinetic properties were computed on online server PreADMET (https://preadmet.bmdrc.kr/). In the current investigations our virtual screening based on structure similarity search afforded 1699 compounds which were subjected for molecular docking with COX-2. These compounds were filtered based on binding affinity and binding poses which yielded 699 compounds. Further, sorting out based on drug-like properties produced a list of seven compounds (H1, H2, H3, H4, H5, H6 and H7). The in silico pharmacokinetic study revealed that these compounds possess good human intestinal absorption and moderate permeability through Caco-2 cell. Further, the Cbrain/Cblood ratio of these compounds indicate moderate penetrability of CNS except H3 and H5. The computational prediction of these compounds as substrates for P glycoprotein showed that H3 may act as both inhibitor and substrate for P glycoprotein. Moreover, molecular docking of H and its selected top hits revealed that all the ligands possess moderate to good binding affinity (-7.6 to -8.9 Kcal/mol) and associate with Val509 via hydrophobic interaction. Ligands H, H1, H2, H3, H4, and H7 can accommodate their aromatic ring inside the side pocket of COX-2 which is similar for accommodation of sulfonamide and methyl sulfone groups for celecoxib and rofecoxib, respectively. Therefore, it is expected that these ligands may exert their analgesic action by selectively blocking the biosynthesis of prostaglandins mediated by COX-2. Our computed properties may assist to develop hispolon derivatives with better pharmacokinetic and COX-2 inhibitory activity.