Cancer is an abnormal growth of cells which could migrate from its place of origin to other parts of the body. It is one of the most serious disease on which widespread research work has been going on. Computer aided drug designing has helped in the identification of potential leads that can be used for the development of a drug. Plumbagin is a naphthoquinone derivative from Plumbago zeylanica roots which possess strong anticancer properties. Plumbagin has been shown to produce inhibitory effects on multiple cancer-signaling proteins. However, binding mechanism and molecular interactions have not been elucidated yet for most of the target proteins. In this investigation, an attempt was done to explore the binding mechanism of plumbagin against cyclin-dependent kinases (CDK) receptor using molecular docking. The least binding energy of plumbagin with CDK6 was found to be − 6.18 kcal/mol. The molecular simulation suggests that plumbagin has potential binding affinities with CDK6 and its interactions with CDK6 was quite stable during the whole period of simulation run. It was also found that plumbagin obeys Lipinski’s Rule of 5 and has drug likeness proved by ADMET analysis. As plumbagin is a natural compound, it has reduced side effects and these results would be useful for cancer treatment.