Scaffold analysis revealed that the most frequent scaffolds were benzene, followed by flavone and flavylium. Diversity analysis and coverage in chemical space showed that the compounds in the Epi Food Chemical Database have an overall large diversity compared to compounds in FooDB. In addition, we identified two main groups of compounds; the first, with continuous structure-activity relationships, aka, fulfill the similarity principle: compounds with similar chemical structures have similar epigenetic activity profiles. The second group of compounds can be considered pseudo-activity cliffs (similar structures but very different epigenetic activity profiles). This work serves as a justification for further experimental testing of the compounds that form pseudo-activity cliffs. They may have similar activity to their analogous compounds. This work contributes to the further advancement of a systematic analysis of food and natural product chemicals with epigenetic activity using chemoinformatic approaches.