Cadmium (Cd2+) and copper (Cu2+) are considered immunotoxic metals and their presence in combination in the aquatic environment may cause effects on shrimp species as Litopenaeus vannamei. Thus, this research evaluates the combined effects of Cd2+ and Cu2+ on shrimp inoculated with Vibrio harveyi bacteria. The experiments were performed at 96-h of exposure to sublethal concentrations of both metals. No mortality was observed in organisms exposed to the sum of Criterion of Continuous Concentration (ΣCCC) in Cd + Cu mixture and those inoculated with V. harveyi. Higher clotting times were recorded in Cd + Cu + V. harveyi treatment at higher metal concentrations. No significant differences (P > 0.05) were recorded in hemocyanin content between shrimp exposed to metals and those experimentally infected. Significantly higher (P < 0.05) total hemocyte count (THC) was recorded at 96 h exposure in the ΣCCC and 10% treatments of Cd + Cu + V. harveyi experiment. Regarding Cd + Cu + V. harveyi bioassay, the highest phenoloxidase (PO) activity was recorded in shrimp inoculated with V. harveyi (0.326 ± 0.031 PO units/mg protein) at 96-h exposure. The lowest PO activity was observed in organisms exposed to Cd + Cu + V. harveyi. Regarding superoxide dismutase (SOD) activity, shrimp exposed to higher metal concentrations at 96 h showed the lowest hemolymph activity (6.03 ± 0.62 SOD units/mL). Protein decrease was observed in organisms exposed to metal mixture. The results showed that L. vannamei could be more susceptible to V. harveyi when exposed to Cd + Cu.