Since the grain size and microstrain amounts in the microstructure affects the final properties, studying the effect of annealing parameters on grain size and microstrain using experimental data and statistical models is important for designing strong metals. In this work, nanostructured Cu powder prepared by high-energy ball milling was annealed at various conditions. The effects of annealing time and temperature on the grain size and microstrain were investigated using response surface methodology. X-ray diffraction was conducted to measure the grain size and microstrain. In addition, scanning electron and transmission electron microscopies were used to characterize the produced powder. The results showed that the models were predicting the responses, accurately. The annealing temperature was the most effective parameter to minimize the microstrain as a result of concurrent existence of recovery, recrystallization, and grain growth. The developed models can be used for predicting grain size and microstrain, and therefore they can be accepted as an economical way to extract arbitrary information about grain growth kinetics of annealed Cu nanostructured powders.