'epigenomics' originates from Greek and Modern scientific coinage, specifically the Greek prefix 'epi-' (ἐπί) meaning 'on, upon' and the word 'genome' (from Neo-Greek/modern coinage based on Greek 'genos') where 'genos' meant 'birth, race, kind', combined with the suffix '-omics' indicating the study of complete sets.

'epigenomics' developed from the mid-20th-century term 'epigenetics' (coined by C. H. Waddington in 1942) and the derivative 'epigenome' (referring to the totality of epigenetic marks); with the rise of high-throughput genome-wide methods in the late 20th and early 21st centuries the term 'epigenomics' emerged to denote genome-scale study.

Initially related to Waddington's concept of 'epigenetics' about developmental regulation and gene–environment interactions, the usage evolved into the modern technical sense of genome-wide analysis and mapping of epigenetic modifications.