<p>Cadmium (Cd) and copper (Cu) pollution in aquatic environments impacts fish health and threatens the sustainability of the aquaculture industry. In this context, this research was designed to investigate the effects of co-exposure to Cd and Cu stress on health status responses in sea bass (<i>Dicentrarchus labrax</i>) at different durations. The fish were allocated into 4 groups with the same initial weight (26.14 ± 1.16&#xa0;g). The first group (control group) was maintained without Cd or Cu, whereas the second group (W1), third group (W2), and fourth group (W3) were exposed to Cu and Cd at 0.7 and 0.5&#xa0;mg/L, respectively, for 7, 14, and 21 days. The results showed that, with increased co-exposure time, tissue gradually accumulated these metals; the liver had the highest concentration, followed by the gills, spleen, and muscle. At 7 days, the activity of digestive enzymes and hematobiochemical indices was enhanced, then negatively affected at 14 and 21 days, respectively. Furthermore, Immune (Lysozyme activity, Phagocytic activity, and Phagocytic index) and oxidative indices (SOD, CAT, and GPX) responses showed a significant increase after co-exposure to metals at 7 days, followed by a gradual decrease at 14 days, and reached their lowest values at 21 days. Conversely, the MDA level decreased after co-exposure to metals, reaching its highest level at 21 days. Pro-inflammatory and stress markers (IL-8, IL-1β, TNF-α, and HSP70) were negatively affected at 21 days of co-exposure compared with other time points. The tissues showed marked histological abnormalities after co-exposure to Cu and Cd at 14 to 21 days, compared with the 7-day and control groups. Overall, these results indicate that <i>D. labrax</i> is affected over time by co-exposure to Cd and Cu, underscoring the need for regular monitoring of metal co-exposure to protect fish health and support sustainable aquaculture.</p>