The aim of this study was to determine the tolerance to metals (Zn, Cu) and drought of male and female Salix × fragilis L. under isolated and combined treatments, and to assess the metal uptake and profiling of metabolic plant responses. The 14-day experiment was performed in a hydroponic system, and metals were applied at 1.5 mM in a Knop’s solution. Drought simulation was achieved by adding sorbitol at a moderate level (200 mM). Isolated Zn treatment enhanced plant growth, more pronouncedly in females. Equimolar Cu treatment caused diverse reactions, and females exhibited significantly higher tolerance. Male specimens were less tolerant to isolated drought and to combined drought and metal presence. The highest contents of Cu and Zn were found in roots, compared to the aboveground tissues (wooden rods and leaves), of both female and male metal-treated plants. Simultaneously applied drought limited Zn accumulation in roots and elevated its translocation to leaves while increasing Cu accumulation, predominantly in females showing higher tolerance. Both isolated and combined drought and metals reduced leaf water content, caused the allocation of mineral nutrients (Ca, Mg, K, and Na), and affected metabolism in a stressor-specific and sex-dependent manner. For males, Cu accumulation in the leaves was significantly correlated with the majority of metabolites, while for both sexes, kaempferol and salicylic acid were strongly correlated, indicating their role in tolerance against the metal. The obtained results are an excellent starting point for the practical use of male and female Salix × fragilis L. in areas heavily polluted with Cu or Zn and exposed to drought, for the purpose of their recultivation.