The Esmoriz–Paramos lagoon is one important ecosystem located in the Northwest coast of Portugal. This study is concerned with the assessment of pollution of the lagoon contributed by urban, industrial and agricultural activities. The parameters selected for this aim were the occurrence of hepatic histological alterations and plasma blood biochemistry in Liza saliens, the dominant fish in this lagoon. Blood parameters were compared between mullets collected from the lagoon and from the sea and included plasma enzyme activities (aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP)), glucose (GLU) and total protein (TP). A positive relationship between hepatocyte vacuolization index and hepatosomatic index was found, suggesting that lipid accumulation could have contributed to the increase of liver weight. The hepatic alterations recorded included general diagnostic categories and additionally large areas of heterogeneous parenchyma, composed of hepatocytes with different spectrum of vacuolization. Liver histopathological evaluation revealed a sample prevalence of 34% for heterogeneous parenchyma, 31% for foci of necrosis and 9% for non-neoplastic lesions. No neoplastic lesions were found. Livers with heterogeneous parenchyma showed higher Cu and Zn content than livers without this category of lesion, suggesting that metals accumulated could trigger this hepatic alteration. AST was higher in mullets from the lagoon than in mullets from the sea, but no differences in ALP and ALT were found, suggesting a change in protein metabolism as an adaptive response to metals exposure. The higher glucose and protein contents observed in fish caught in the lagoon are consistent with a stress response and the measurement of plasma AST activity could be a sensitive indicator of lagoon fish stress. In conclusion, Esmoriz–Paramos lagoon biomonitorization, using indicator species will proceed to assess the impact of the restoration program under development by the Portuguese government.