Trace elements are a persistent threat to Mediterranean coastal ecosystems, where anthropogenic pressures continue to increase. Although biomarker-based approaches are widely used in marine biomonitoring, species-specific ecotoxicological data remain limited. The hermit crab Clibanarius erythropus (Latreille, 1818), a widespread Mediterranean detritivore chronically exposed to sediment-associated trace elements, has never been ecotoxicologically investigated. In this study, the first integrated assessment of the sensitivity of C. erythropus to copper (Cu) and cadmium (Cd) was conducted. Acute toxicity (96-h median lethal concentration, LC₅₀) was assessed along with inductively coupled plasma mass spectrometry (ICP-MS) quantification of hepatopancreatic bioaccumulation. Sublethal responses were evaluated in the entire soft tissues of the abdomen, including the hepatopancreas, after 24, 48, and 96 h of exposure to ½ LC₅₀ (high), ¼ LC₅₀ (medium), and ⅛ LC₅₀ (low). This study provides a specie-specific assessment in C. erythropus, confirming the expected higher toxicity of Cd over Cu as demonstrated by significantly lower Cu 96-h LC₅₀ values and greater bioaccumulation (LC₅₀ = 4.96 mg L-1 for Cd vs. 46.3 mg L-1 for Cu; 914 ± 75.0 mg kg-1 for Cd vs. 421 ± 66.8 mg kg-1 for Cu). With both metals, sublethal exposure triggered a significant increase in reactive oxygen species (ROS) and glutathione depletion, accompanied by the induction of alkaline phosphatase, esterase, and peroxidase activities. These findings establish the first species-specific ecotoxicological baseline for C. erythropus and support its potential use as a bioindicator in coastal monitoring programs under the Water Framework Directive (WFD) and Marine Strategy Framework Directive (MSFD).