The bioaccumulation and toxic effects of synthetic phenolic antioxidants (SPAs) in aquatic ecosystems are of growing concern due to their widespread use and potential environmental persistence. This study investigated the detoxification and toxicological impacts of 2,6-ditert-butyl-4-methylphenol (BHT), a representative SPAs, on clams Ruditapes philippinarum using environmentally relevant exposure concentrations. BHT bioaccumulation was observed in both gills and digestive glands, with higher levels in the latter. Detoxification processes were induced, evidenced by upregulated phase I and phase II detoxification enzymes and genes. However, the antioxidant defense system was suppressed, suggesting a potential adaptive strategy to balance detoxification and antioxidant needs. Toxic effects included biomacromolecular damage (lipid peroxidation, protein carbonylation, and DNA damage), neurotoxicity (inhibition of cholinesterase activities), respiratory toxicity (induction of key enzymes and genes involved in oxidative phosphorylation and glycolysis), and immunotoxicity (suppression of immune parameters). Potential biomarkers for BHT contamination were identified, including lipid peroxidation, protein carbonylation, cholinesterase activity, and key detoxification-related enzymes and genes. Further validation is needed under field conditions and considering other potential stressors. This study demonstrates that BHT poses significant systemic toxic effects on bivalves, highlighting the need for monitoring and controlling SPA pollution in marine environments to protect ecosystem health and human well-being.