This study brings a new viewpoint based on multiple-tissue analyses to form the basis for a predictive mode of mercury accumulation dynamics in fish body under field conditions. Total mercury (T–Hg) was determined in key tissues of Liza aurata captured along an estuarine contamination gradient, displaying the following hierarchy: kidney > liver > muscle > brain > gills > blood. Brain was the tissue that better reflected the mercury contamination extent, closely followed by liver and muscle. Organic mercury (O–Hg) measured in muscle and liver represented more than 85% and less than 30% of the T–Hg, respectively. The lowest O–Hg percentage was found in the most contaminated area, for both muscle and liver. Mercury distribution and accumulation patterns showed dependence on the specific tissue. The high mercury levels found in organs involved in vital physiological processes point out the risk to autochthonous fish fauna. Human risk associated to the ingestion of fish living in the surveyed areas cannot be excluded.