This study was designed to investigate the molecular (transcriptional expression), biochemical (oxidative stress and neurotoxicity), and histopathological effects of metal contamination in the gill of clams (Ruditapes decussatus) sampled from the Tunis lagoon. The concentrations of five heavy metals (Cd, Pb, Hg, Cu, and Zn) in surface sediments and their accumulation in soft tissues of R. decussatus were evaluated in three sites (Z1, Z2, and Z3). A metal contamination state of Tunis lagoon sediments was noted with spatial variations with relatively high levels at Z2. Biomarker analyses showed an increase in glutathione S-transferase and catalase activities and lipid peroxidation levels and a decrease in acetylcholinesterase activity in the studied sites. Molecular investigation showed a significant overexpression of: cytochrome c oxidase subunit I, ribosomal RNA 16S, Cu/Zn superoxide dismutase, heat shock protein 70, and metallothioneins in the three sampling sites. Moreover, our data were correlated to severe and diverse histopathological alterations in the clam gills. The principal component analysis showed that the Z2 region is more affected by metal contamination than Z1 and Z3 regions. Current field results suggest the use of several combined biomarkers at different cell levels instead of individual ones in monitoring programs.Read less <