Current guidelines tend to limit fish consumption based on mercury (Hg) or monomethylmercury (MeHg) content in fish flesh, without considering the presence of antagonist chemical elements that could modulate Hg toxicity. However, it is difficult to assess the potential for antagonistic interactions of these elements since their covariation within muscle tissues is poorly known. Here we present the first study simultaneously mapping multiple metal(oid)s (Hg, As and Se), lipids and proteins in fish fillets in order to assess the magnitude of intra-organ variability of metals and the potential for antagonistic interactions. We mapped two fish species (Striped Bass and Northern Pike) with contrasting muscular structure with respect to the presence of white, intermediate and red muscles. In individual Striped Bass muscle tissues, metals varied on average by 2.2-fold. Methylmercury and selenium covaried strongly and were related to protein content as assessed by % N; arsenic was inversely related to these elements and was associated with the lipid fraction of the muscle. In Pike, no such relationship was found because the contents in proteins and lipids were less variable. Arsenic speciation revealed that arsenobetaine and arsenolipids were the only As species in those fish species, whereas the toxic inorganic As species (As3+) was under the detection limit. Arsenobetaine was related to % N, whereas arsenolipids covaried with % lipids. Elemental associations found with muscle lipids and proteins could help explain changes in bioaccumulation patterns within and between individuals with potential implications on fish toxicology, biomonitoring and human consumption guidelines.