Araruama lagoon is one of the largest permanent hypersaline lagoons in the world and has been impacted for twenty years by sewage dumping. In early 2005, a Prasinophyceae (Pseudoscourfieldia sp.) phytoplankton bloom occurred, leading to fish mortality during subsequent summers (2006 and 2007). In this context, the aim of the present study was to accompany this historical period through the use of biochemical biomarkers in mullet (Mugil liza) during and after the algal bloom. Mullet were collected from Araruama Lagoon in June and July 2005 and August 2007, as well as from a reference lagoon with no algal blooms, Saquarema Lagoon. Several enzymatic activities in liver were analyzed, namely glutathione peroxidase (GPX), catalase (CAT), total glutathione S-transferase (GSTt), specific GSTπ (pi) and GSTμ (mi) classes and ethoxyresorufin-O-deethylase (EROD), as well as muscle acetylcholinesterase activity (AChE). In 2005, only EROD activity was significantly increased at Araruama Lagoon, indicating induction of the biotransformation enzyme system (CYP 1A1). GSTπ, on the other hand, was lower in the Araruama Lagoon, especially in 2005, when compared to mullet from Saquarema lagoon (reference area). These results highlight the importance of developing actions that go beyond the physical-chemical monitoring of these environments, since the study of ecological relationships and the physiology of organisms affected by algal blooms also include biochemical parameters to evaluate new approaches to icthyotoxicity.