A novel series of thiophene hybridized thiadiazolyl Schiff bases (TTS) were designed and synthesized using copper nitrate (CuII) catalyzed synthesis of Schiff bases and their subsequent ferric chloride (FeIII) catalyzed cyclization into thiadiazoles. The design of molecules was inspired by the well-documented anti-inflammatory properties of thiadiazoles, Schiff bases and thiophene. Based on information from mass spectroscopy, IR, 1H and 13C NMR measurements, the structures of the recently synthesized compounds were determined. The purpose of molecular docking was to better understand the interactions between drug candidates and COX-1 (PDB ID: 3KK6) and COX-2 (PDB ID: 3Q7D) inflammation-related targets. Compounds 3a-f showed a more stable binding complex with COX-2 (-8.09 to -9.13 kcal/mol) when compared to COX-1 (-4.86 to -5.94 kcal/mol). Additionally, the carrageenan-induced rat paw oedema model was used for the in vivo analysis and compound 3a demonstrated excellent anti-inflammatory activity when compared to the reference drug, diclofenac. Interestingly, the mRNA expression analysis using qRT-PCR demonstrates a specific suppression of COX-2 as compared to COX-1, further supporting the earlier findings. Altogether, the findings could provide an opportunity for these compounds to be developed as novel lead molecules for rational alternatives of NSAIDS.