Curcumin is the most effective therapeutic agent and has anticancer activity. But due to the diketone moiety, it has a weak pharmacokinetic profile. The aim is to identify the best candidate from the designed mono‐carbonyl curcumin derivatives that bind to the T790M mutated crystal structure. Three distinct EGFR crystal structures, including the wild‐type (PDB: 1M17 and 4I23) and T790M mutant (PDB: 6LUD), were subjected to comparative molecular docking. Focusing on the T790M mutated crystal structure (6LUD), NME 3 was then studied for molecular dynamics. Designated derivatives were found to have good ADMET properties. Among all the New Molecular Entities, NME1, 2, and 3 were found to have good binding affinity towards 1st, 2nd, and 3rd generation EGFR crystal structures and a greater dock score than standard curcumin. Therefore, NME 3 was further studied for molecular dynamics, and results were compared with those of the co‐crystallised ligand S4 (Osimertinib). It was found that the RMSD (1.8 Å), RMSF (1.45 Å ), and radius of gyration (4.87 Å) values of NME 3 were much lower than those of S4 (Osimertinib). All this confirms that our designed NME 3 is more stable than reference S4 (Osimertinib).