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[Display omitted] • 1,3,4-oxadiazole-thiazolidine-2,4-dione hybrid compounds (TOT-1 to 15) were synthesized, characterized and screened for various biological activities. • Single-crystal X-ray diffraction data was collected for the intermediate compound, TOT and its structure was proposed. • The compounds, TOT 12–15 exhibited significant anti-cancer activity. • Molecular docking studies were carried out. Two synthetic methods were proposed for the preparation of a new series of thiophene-1,3,4-oxadiazole-thiazolidine-2,4-dione hybrids (TOT-1 to 15) and their structures were elucidated based on spectral data. Studies on cytotoxicity, ROS, cellular uptake and interactions of TOT-14 with calf thymus DNA were carried out. Anticancer activity of compounds, TOT-1 to 15 on breast cancer (MCF-7) cell lines was investigated. The IC 50 values for the standard, epirubicin hydrochloride and TOT-12, 13, 14 and 15 were found to be 6.78, 5.52, 6.53, 4.83 and 5.57 µg/mL, respectively. Notably, TOT-14 exhibited a remarkable antiproliferative activity with a strikingly selective inhibitory effect compared to standard. This specific selectivity could be attributed to the synergistic effect of increased cellular uptake and generation of higher ROS in cancer cells after irradiation. The binding constant of 4.25 x 103 M−1 indicated the moderate interaction between TOT-14 and ct-DNA. The docking score of TOT derivatives was substantially identical to the docking score of epirubicin hydrochloride. The designed molecules complied with the requirements for drug-likeness and ADME. [ABSTRACT FROM AUTHOR]