The risk assessment of mercury (Hg), in both wildlife and humans, represents an increasing challenge. Increased production of reactive oxygen species (ROS) is a known Hg-induced toxic effect, which can be accentuated by other environmental pollutants and by complex interactions between environmental and genetic factors. Some epidemiological and experimental studies have investigated a possible correlation between brain tumors and heavy metals. Epigenetic modifications in brain tumors include aberrant activation of genes, hypomethylation of specific genes, changes in various histones, and CpG hypermethylation. Also, Hg can decrease the bioavailability of selenium and induce the generating of reactive oxygen that plays important roles in different pathological processes. Modification of homeostasis of metals can induce ROS excess and cause lipid peroxidation, alteration of proteins, and DNA damage. In this review, we highlight the possible relationship between Hg exposure, epigenetic alterations, and brain tumors.