Abstract A new series of heterofused thiazolo/pyrazinedione hybrids were designed, synthetized and their cytotoxicity potential was evaluated against different cancer cell lines. Besides, drug‐likeness and in silico ADME/Tox studies were carried out using free server tools. The heterofused hybrids 3‐aryl‐thiazolo[3,4‐ a ]pyrazine‐5,8‐diones 3 a – o were obtained in moderate to good yields (30–80 %) and with high diastereomeric ratio. Notably, hybrids 3 g – j showed good cytotoxic effect on Hep‐G2 cancer cells IC50 (28.6±4.9 μM, 54.2±15.4 μM, 95.2±1.9 μM, 68.6±1.6 μM) respectively, while compounds 3 l – m were cytotoxic on B16F10 melanoma cancer cells IC50 (20.9±5.3 μM, 30.0±6.4 μM). Furthermore, the new compounds were relatively non‐toxic on Vero cells. In silico drug‐likeness and ADME/Tox studies suggest optimal pharmacokinetic profile for all hybrids. Altogether, these new heterofused hybrids could be considered as promising scaffolds in cancer chemotherapy.