A new series of hybrid structures 14a–l containing thiohydantoin as anti-cancer moiety and pyrazole core possessing SO2Me pharmacophore as selective COX-2 moiety was designed and synthesized to be evaluated for both anti-inflammatory and anti-cancer activities. The synthesized compounds were evaluated for their COX inhibition, in vivo anti-inflammatory activity, ulcerogenic liability, in vitro cytotoxic activity and human topoisomerase-1 inhibition. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. Also, all derivatives were significantly less ulcerogenic (ulcer indexes=2.64–3.87) than ibuprofen (ulcer index=20.25) and were of acceptable ulcerogenicity when compared with the non-ulcerogenic reference drug celecoxib (ulcer index=2.99). Regarding anti-cancer activity, most of the target derivatives showed activities against A-549, MCF-7 and HCT-116 cell lines (IC50=5.32–17.90, 3.67–19.04 and 3.19–14.87 μM respectively) in comparison with doxorubicin (IC50=0.20, 0.50 and 2.44 μM respectively). Compound 14a inhibited the human topoisomerase-1 with IC50=29.7 μg/ml while 14b and 14c showed more potent inhibitory activity with IC50=26.5 and 23.3 μg/ml. respectively in comparison with camptothecin (IC50=20.2 μg/ml). Additionally, COX-2 and human topoisomerase-1 docking studies were carried out to explain the interaction of the synthesized hybrid structures 14a–l with the target enzymes.