In this study, Cu/Ni and Cu/Al multilayers, with individual layer thickness varying from 25 nm to 200 nm, and co-sputtered Cu-Ni and Cu-Al single layer films were deposited at room temperature via magnetron sputtering and further annealed from 100 °C to 300 °C. The mechanical and microstructural properties of the as-deposited and annealed samples were characterized by nanoindentation, x-ray diffraction, and scanning electron microscopy. Both multilayer systems exhibit an increase in hardness with increasing annealing temperature. However, the Cu/Ni system shows a gradual and moderate hardness increase (up to 30%) from room temperature to 300 °C, while the Cu/Al system displays a sharp hardness surge (~150%) between 125 °C and 200 °C. The co-sputtered Cu-Ni and Cu-Al samples consistently demonstrate higher hardness than their multilayered counterparts, albeit with distinctly different temperature dependence—the hardness of Cu-Ni increases with annealing temperature while Cu-Al maintains a constant high hardness throughout the entire temperature range. The distinct thermal strengthening mechanisms observed in the two metallic multilayer systems can be ascribed to the formation of solid solutions in Cu/Ni and the precipitation of intermetallic phases in Cu/Al. This study highlights the unique advantage of intermetallic strengthening in metallic multilayer systems.