This study investigated the impact of seasonal organochlorine pesticide pollution on the physiological responses of Donax trunculus at Aghroud Beach during 2009 and 2010. Significant findings include the detection of six pesticides, with Endosulfan S being the most prevalent, reaching concentrations up to 62.63 ng/g dry weight. Biomarker analysis revealed notable seasonal variations, with the highest Acetylcholinesterase (AChE) activity in winter 2009 and the lowest in spring 2010. Glutathione S-transferase (GST) activity peaked in autumn 2009, while Catalase (Cat) showed maximum activity in autumns of 2009 and 2010. Malondialdehyde (MDA) levels were highest in summer 2010, indicating increased oxidative stress and lipid peroxidation during this period. Integrated Biomarker Response (IBR) values were highest in autumns, suggesting significant pollution stress. Principal Component Analysis (PCA) revealed strong correlations: a synergy between GST and Cat, and positive links between MDA and lipids, as well as AChE and Endosulfan B. This study highlights the efficacy of using integrated biomarker responses to assess environmental health and stresses the importance of autumn and summer monitoring due to higher pollution impacts.