Selenium (Se) is a beneficial element for plants, and can be used to mitigate the toxicity of heavy metals. However, the detoxification of Se in macroalgae, a crucial part of aquatic ecosystem productivity, has rarely been reported. In the present study, a red macroalga Gracilaria lemaneiformis was exposed to non-essential metal cadmium (Cd) or essential metal copper (Cu) with addition of different levels of Se. We then examined the changes in growth rate, metal accumulation, metal uptake rate, subcellular distribution, as well as thiol compound induction in this alga. Se addition alleviated Cd/Cu-induced stress in G. lemaneiformis by regulating cellular metal accumulation and intracellular detoxification. Specifically, supplementation of low-level Se displayed a significant decrease in Cd accumulation, and thus alleviated the growth inhibition induced by Cd. This may be caused by the inhibitory effect of endogenous Se instead of exogenous Se on Cd uptake. Although Se addition increased bioaccumulation of Cu in G. lemaneiformis, the important intracellular metal chelators, phytochelatins (PCs), were massively induced to alleviate Cu-induced growth inhibition. High-dose Se addition did not deteriorate but failed to normalize the growth of algae under metal stress conditions. Reduction in Cd accumulation or induction of PCs by Cu could not suppress the toxicity of Se above safe levels. Se addition also altered metal subcellular distribution in G. lemaneiformis, which might affect the subsequent metal trophic transfer. Our results demonstrated that the detoxification strategies of Se between Cd and Cu were different in macroalgae. Elucidating the protective mechanisms of Se against metal stress may help us better apply Se to regulate metal accumulation, toxicity, and transfer in aquatic environment.