Recent studies have shown that monoterpenes exhibit antitumor activities and suggest that these compounds are a new class of cancer chemo-preventive agents. Limonene, a main constituent of orange and citrus peel oils has been reported to exert antitumor activity against mammary gland, lung, liver, stomach and skin cancers in rodents whereas, geraniol, a principal constituent of Geranium and Ocimum inhibits the growth of human colon cancer cells. Prenylation of proteins is essential for progression of cells into the S phase and involves post-translational covalent attachment of a lipophilic farnesyl or geranylgeranyl isoprenoid group to numerous proteins. Suppression of prenylation of proteins leads to inhibition of DNA synthesis. Further, epidemiologic evidences suggest that suppression of hydrophilic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, a key enzyme of mevalonate biosynthesis, leads to reduction of the mevalonate pool and thus limits protein isoprenylation. Geraniol and limonene inhibit the activity of HMG-CoA reductase subsequently reducing the possibility of cancer growth. In the present work, we analyzed binding affinity of limonene and geraniol with HMG-CoA and explored mechanism of interaction using in silico approaches. The binding positions were verified according to their energy, PMF (Potential of Mean Force) value, PLP (Piecewise Linear Potential) value and Ligand Internal energy. It was found that limonene had greater binding affinity with the receptor suggesting better antitumor agent in comparison to geraniol.