Top predators such as most shark species are extremely vulnerable to amassing high concentrations of contaminants, but not much is known about the effects that the contaminant body burden imparts on these animals. Species like the blue shark (Prionace glauca) are very relevant in this regard, as they have high ecological and socioeconomic value, and have the potential to act as bioindicators of pollution. This work aimed to assess if differences in contaminant body burden found in blue sharks from the Northeast Atlantic would translate into differences in stress responses. Biochemical responses related to detoxification and oxidative stress, and histological alterations were assessed in the liver and gills of 60 blue sharks previously found to have zone-related contamination differences. Similar zone-related differences were found in biomarker responses, with the sharks from the most contaminated zone exhibiting more pronounced responses. Additionally, strong positive correlations were found between contaminants (i.e., As, PCBs, and PBDEs) and relevant biomarkers (e.g., damaged DNA and protective histological alterations). The present results are indicative of the potential that this species and these tools have to be used to monitor pollution in different areas of the Atlantic.