Aim Based on the structural features of both lonazolac and celecoxib, as an attempt to improve COX-2 selectivity, a series of novel di-aryl-chalcone derived pyrazole (16a-l) was designed, synthesized, and evaluated for its COX-2 selective anti-inflammatory inhibitory activity. Results Derivatives 16d, 16f, 16k, and 16l displayed approximately two-folds greater COX-2 inhibitory effects (IC50) than celecoxib, scoring IC50 of 0.446, 0.686, 0.348, and 0.771 μM, respectively, compared to 0.685 μM for celecoxib. 16d, 16f, 16k, and 16l compounds additionally demonstrated remarkable COX-2 selectivity index (S.I.) in the range of (S.I. = 25.56–70.40) in contrast to celecoxib (S.I. = 24.09). Moreover, In-vivo anti-inflammatory activity study of the most potent derivatives 16d, 16f, and 16k reinforced the in-vitro results. For instance, compound 16k induced 53% edema inhibition at the 5th hour, comparable to that observed with celecoxib. The compounds 16d, 16f, 16k, and 16l resulted in significant attenuation of pro-inflammatory mediators (PGE2, IL-6, TNF-α, and NF-Kβ) that produced from carrageenan-induced edema. Molecular docking and dynamics results of derivatives 16d, 16f, 16k, 16l indicate to their relatively stable interactions within the COX-2 active site. Conclusions The present work paves the way for further development of potent selective COX-2 inhibitors with anti-inflammatory activity.