Novel series of thiadiazole derivatives were designed and synthesized for evaluation as selective COX-2 inhibitors in-vitro and investigated in-vivo as anti-inflammatory and analgesic agents against carrageenan-induced rat paw oedema model in irradiated rats, since its well-known that ionizing radiation plays an important role in exaggerating the inflammatory responses in experimental animals. Ulcerogenic activity and acute toxicity were evaluated for the most potent compounds. In order to understand the binding mode of the synthesized compounds into the active site of COX-2 enzyme, docking study was performed. Most of the tested compounds showed high inhibitory ability to COX-2. Among them, thiadiazole derivatives bearing sulfonamide moieties 7b,c and 13c,e were the most potent COX-2 inhibitors with extremely high selectivity index (SI) compared to celecoxib, they showed high safety margin on gastric mucosa with no ulceration effect and they were found to be non-toxic in experimental rats. Docking study showed similar orientation of these compounds as celecoxib within the active site of COX-2 enzyme and their ability to emerge deeply in the additional pocket and binding with Arg513 and His90 the key amino acids responsible for selectivity.