In an attempt to improve and develop biologically potential anticancer agents, synthesis of new anticancer agents are in progress. This study focused on the synthesis of novel compounds and examined the anticancer potentials of lung cancer cell line (A549), breast cancer cell line (MCF-7) and liver cancer cell line (HepG2) using MTT assay. Molecular docking and ADME studies were performed for the anticancer compounds. A novel set of indeno[2,1-e][1,3,4]oxadiazinone 2a-f was designed and constructed via a reaction of ninhydrin, hydrazine hydrate and the appropriate isothiocyanate. The anticancer impact of the newly prepared compounds 2a-f was assessed in vitro against A549, MCF-7 and HepG2 cell lines. The cyclohexylmethylaminoindenooxadiazinone derivative 2f was the most active candidate towards A549 and HepG2 with IC50 (64.88 and 39.18 µg/ml), respectively. A molecular docking study was done within EGFR active site to predict the binding mode of the novel compounds. Both compounds 2b and 2f recorded high binding energy scores with the excellent fitting with the active site. ADME study results displayed compounds 2b and 2f registered positive values showing good drug-likeness behavior. Multiple linear regression analysis was used to construct consistent QSAR models based on quantum mechanics-derived chemical descriptors. The experimental anticancer activity data correlated well with the expected one. Hence, it is possible to speculate that the novel compound 2f could be considered n anticancer lead compound.