One of the main impacts expected in CO2 leakage scenarios from carbon capture and storage in sub-seabed geological structures is the acidification of the environment. In the present work, laboratory-scale experiments were performed to investigate the effects of seawater acidification (pH 7.0, 6.5, 6.0, and control) in native clams (Scrobicularia plana) over 21 days of exposure. For this purpose, a battery of biomarkers (GSI, EROD, GST, GPX, LPO, and DNA damage) were analysed in the digestive glands of individuals collected on days 7, 14 and 21. Seawater acidification significantly affected the average life span of S. plana, and both the biomarkers analysed and the multivariate analysis approach demonstrated that seawater acidification induced a strong oxidative stress response in the clam. Oxidative stress overwhelmed the capacity of S. plana to defend its cells against it, resulting in DNA damage. Furthermore, the decline in the population of S. plana in their natural habitat could lead to a reduction in available food resources for avifauna, ichthyofauna, and for the local economy because this clam is a commercial species in the south of Europe.