Studying the cumulative impacts of interacting stressors is essential for predicting ecosystem-wide risks from anthropogenic stressors, yet multi-stressor experiments remain scarce. Here, we investigated how lead (Pb) contamination influences survival and cross-tolerance to salinity and thermal stress in Arctic blue mussels (Mytilus edulis). Mussels were exposed to environmentally relevant Pb concentrations, followed by sequential exposure to varying salinities (5–25) and aerial temperatures (5–36 °C). Survival patterns were assessed, and transcriptomic responses were analysed using RNA sequencing. Heat-induced mortality occurred across treatments, and Pb exposure elevated baseline mortality. However, elevated tissue Pb concentrations significantly attenuated temperature-driven mortality, indicating partial cross-tolerance between contamination and thermal stress. Reduced salinity increased vulnerability to heat stress and weakened the protective effect of Pb. Transcriptomic analyses revealed upregulation of cellular stress-response pathways, including detoxification-related genes, consistent with transcriptional front-loading mechanisms underpinning cross-tolerance. Gene expression responses were modest overall, reflecting the high physiological plasticity of Mytilus mussels. Our findings demonstrate that pollution can alter thermal sensitivity in non-additive ways, complicating predictions of organismal responses to environmental changes. Thus, accounting for multi-stressor interactions is critical to understand species resilience in a rapidly changing world.