Nucleic acid is the key unit and a predominant genetic material for interpreting the fundamental basis of genetic information in an organism and now it is used for the evolution of a novel group of therapeutics. To identify the potential impact on the biological science, it receives high recognition in therapeutic applications. Due to its selective recognition of molecular targets and pathways, DNA significantly imparts tremendous specificity of action. Examining the properties of DNA holds numerous advantages in assembly, interconnects, computational elements, along with potential applications of DNA self-assembly and scaffolding include nanoelectronics, biosensors, and programmable/autonomous molecular machines. The interaction of low molecular weight, small molecules with DNA is a significant feature in pharmacology. Based on the mode of binding mechanisms, small molecules are categorized as intercalators and groove binders having a significant role in target-based drug development. The understanding mechanism of drug-DNA interaction plays an important role in the development of novel drug molecules with more effective and lesser side effects. This article attempts to outline those interactions of drug-DNA with both experimental and computational advances, including ultraviolet (UV) -visible spectroscopy, fluorescent spectroscopy, circular dichroism, nuclear magnetic resonance (NMR), molecular docking and dynamics, and quantum mechanical applications.