© 2020 Elsevier Inc.A series of novel oxo-hydrazone and spirocondensed-thiazolidine derivatives of imidazo[2,1-b]thiazole were synthesized and evaluated for their antioxidant activity. The antioxidant activity of 18 newly synthesized compounds and 12 previously reported compounds bearing similar scaffold, were evaluated by three different methods: inhibition of FeCl3/ascorbate system-induced lipid peroxidation of lecithin liposome (anti-LPO), scavenging activity against ABTS radical and Ferric Reducing Antioxidant Power (FRAP) activity. 4h, 5h, and 6h displayed the highest anti-LPO and ABTS radical removal activity. Also, in FRAP analysis, 4i and 4a displayed the best activity. In addition to the in vitro analysis, docking studies targeting the active site of Human peroxiredoxin 5 (PDB ID: 1HD2) were employed to explore the possible interactions of these compounds with the receptor. Structure-activity relationships, as well as virtual ADME studies, were carried out and a relationship between biological, electronic, and physicochemical qualifications of the target compounds was determined.