The rise in epigenetic studies and its modifications, i.e., heritable alterations in gene expression without changes in DNA sequences, have now been confirmed in diseases. Modifications such as posttranslational histone modifications, DNA methylation and non-coding RNAs in the recent past have led to better understanding of the coaction between epigenetic alterations and human pathologies. Melatonin is a widely-produced indoleamine regulator molecule that influences numerous biological functions within many cell-types. With regard to its broad spectrum of actions, melatonin should be investigated much more with respect to its contribution in the upstream and downstream mechanistic regulation of epigenetic modifications in diseases. This review outlines the findings on melatonin's action on epigenetic regulation in human diseases including neurodegenerative disease, diabetes, cancer and cardiovascular diseases. It summarizes the ability of melatonin to act on molecules such as proteins and transcriptional factors which affects the development and progression of diseases.