Lung cancer is not only the most commonly diagnosed cancer type but also the leading cause of cancer related deaths throughout the world. The advanced methods for lung cancer therapy have focused on the development of new targeted agents. Cyclooxygenase (COX) is one of the most crucial targets for lung cancer therapy. In the current work, new compounds (1-12) containing 1,3,4-oxadiazole and pyrimidine cores within the acetamide framework were synthesized and evaluated for their cytotoxic effects on A549 human lung adenocarcinoma and NIH/3T3 mouse embryonic fibroblast (healthy) cell lines using MTT assay. Compounds 2 and 10 were defined as the most cytotoxic agents in this series (IC50 < 3.9 mu g/mL) compared to cisplatin (IC50 = 26.00 +/- 3.00 mu g/mL) without revealing cytotoxicity to healthy cells. The COX-1 and COX-2 inhibitory profiles of compounds 2 and 10 were also searched for providing a mechanistic insight into their potent antiproliferative effects. Compound 2 inhibited COX-1 and COX-2 dually and significantly (59.52% and 50.59%, respectively), whereas compound 10 exhibited no significant COX-1 and COX-2 inhibition. Molecular docking studies indicated that compound 2 showed its COX-1 and COX-2 inhibitory potencies with favourable interactions in the active sites of COX-1 and COX-2. Both in vitro and in silico assays accentuated that potential, orally bioavailable drug-like compound 2 attracted notice for the COX-targeted anti-lung cancer treatment.