Background: Cancer is continuing to be a major health problem in developing as well as undeveloped countries. It is a leading cause of mortality worldwide accounting for most of deaths. Origin: Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein and mutations that leadto EGFR overexpression or over activity have been associated with a variety of human cancers. Purpose: Synthesis of EGFR inhibitors by inhibiting EGFR kinase activity which competes with its cognate ligands and it may potentially constitute a new class of effective drugs in clinical use or cancer therapy. Experimental work: In the present investigation, we have performed similarity/sub-structure based search of eMolecule database and find out promising benzothiazole derivatives as EGFR inhibitors by several screening criteria including molecular docking and pharmacokinetics features. The best docked pose of each molecule was considered for binding interactions followed by molecular dynamics and binding energy calculation. Result and Discussion:Molecular docking clearly showed that final proposed derivatives potential to form a number of binding interactions. Molecular dynamics simulation trajectories undoubtedly indicated that the EGFR protein become stable when proposed derivatives bind to the receptor cavity. Strong binding affinity was found for all molecules towards the EGFR which substantiated by the binding energy calculation using MM-PBSA approach. Conclusion: In outlook of this, proposed promising benzothiazole derivatives were successfully synthesized and characterized by IR, 1H NMR and Mass spectroscopy techniques. Subsequently, they were screened against MCF-7 cancer cell lines in search of their anticancer potential and H9 and H12 compounds have shown great potential for anticancer therapy.