The Weight-of-Evidence (WOE) approach uses multiple lines of evidence to analyze the adverse effects associated with CO2 enrichment in two stations from the Gulf of Cádiz (Spain) with different contamination degrees. Sediment contamination and metal (loid) mobility, toxicity, ecological integrity, and bioaccumulation from the samples exposed to different acidification scenarios (pH gradient from 8.0 to 6.0) were used in the WOE. The experiments were conducted under laboratory conditions using a CO2-bubbling system. Different integration approaches such as multivariate analyses were used to evaluate the results. The results indicated that the adverse biological effects under pH 6.5 were related to the mobility of dissolved elements (As, Fe, Cu, Ni, and Zn). Furthermore, the pH reduction was correlated to the increase of bioaccumulation of As, Cr, Cu, Fe, and Ni in the tissues of mussels at pH 7.0. The noncontaminated sediment showed environmental degradation related to the acidification at pH values of 7.0; whereas the sediment moderately contaminated showed both environmental risks, caused by acidification and the presence and the increase of the bioavailability of contaminants. The WOE approach supposes an effective tool to identify and distinguish the causes of adverse effects related to the enrichment of CO2 in marine environments.