The nonsteroidal anti-inflammatory drugs like Aspirin, Ibuprofen, Mefenamic acid inhibit Cyclooxygenase(COX) enzyme and control release of inflammatory mediators responsible for inflammation. COX exist as isoenzymes COX-1 and COX-2.Treatment with NSAID has some side effects in different patients such as gastric irritation, ulceration due to inhibition of protective COX-1 enzyme. Larger active site of COX-2 than COX-1 is basis for selectivity in design of selective COX-2 inhibitors. 5-alkyl/ aryl 2-amino 1,3,4-thiadiazole derivatives were designed and which can interact with binding site of the COX-2 enzyme more selectively. These synthesized compounds were confirmed by TLC, MP and spectral analysis. The docking studies were performed using Vlife MDS4.3 software using COX-2 receptor. It has been observed that, phenyl substitution on 1,3,4 Thiadiazole ring shows higher dock score than aliphatic substitution. Further substitution on ortho, meta & para position of phenyl ring with hydroxy group shows remarkable binding affinity for receptor but substitution on ortho, meta & para position of phenyl ring with chloro or nitro group shows reduction in dock score indicating less binding affinity for receptor. The in-vitro anti-inflammatory activity binding was performed using carrageenan induced paw edema method in rats for the compounds which has shown significant dock score .Among the synthesized compounds, 5(2,5 dihydroxy phenyl) 2 amino 1,3,4 thiadiazole has shown significant anti-inflammatory activity.