Although non-steroidal anti-inflammatory drugs (NSAIDs) are still the mainstay of pharmacological treatment of pain and inflammation, their use is limited due to gastrointestinal and cardiovascular toxicity associated with non-selective inhibition of cyclooxygenase (COX) isoforms. Selective cyclooxygenase-2 (COX-2) inhibition has thus remained as important target of medicinal chemistry interest especially in the context of diaryl heterocyclic pharmacophore of celecoxib and lonazolac mimicking pyrazole- and chalcone-based scaffolds. In the present study, 3 representative pyrazole–chalcone hybrid derivatives 14b, 15b and 22 have been subjected to molecular docking investigation with the catalytic active site of human COX-2 (PDB ID: 5IKT) along with Celecoxib and Diclofenac as reference standards. The structures of ligands and proteins were prepared using standard procedure, the docking was performed using AutoDock Vina software using PyRx virtual screening interface and the binding mode of the compounds was visualised using Discovery Studio Visualizer. Among them, compound 22 had the most favourable binding affinity (−10.2 kcal/mol), which made four hydrogen bonds, with Arg120, Tyr355, Ser530 and Phe518 as well as extensive hydrophobic contacts with the secondary pocket of COX-2, and also showed superior binding affinity to celecoxib (−9.6 kcal/mol) and diclofenac (−8.1 kcal/mol) in the same docking conditions. Compounds 14b and 15b had also good and selective binding to the active site with binding energies of −9.8 and −9.4 kcal/mol, respectively. All three derivatives were predicted to be drug-like absorption, distribution, metabolism and excretion (ADMET) by in silico physicochemical and pharmacokinetic screening and were found to be in line with Lipinski's Rule of Five. The results showed that the pyrazole–chalcone hybrid scaffold might be a good starting point for rational design of safer and selective COX-2 inhibitor and the compounds 14b, 15b and 22 are found to be good candidates for further synthetic and biological studies.