In designing microstructural materials systems, one of the key research questions is how to represent the microstructural design space quantitatively using a descriptor set that is sufficient yet small enough to be tractable. Existing approaches describe complex microstructures either using a small set of descriptors that lack sufficient level of details, or using generic high order microstructure functions of infinite dimensionality without explicit physical meanings. We propose a new machine learning-based method for identifying the key microstructure descriptors from vast candidates as potential microstructural design variables. With a large number of candidate microstructure descriptors collected from literature covering a wide range of microstructural material systems, a four-step machine learning-based method is developed to eliminate redundant microstructure descriptors via image analyses, to identify key microstructure descriptors based on structure–property data, and to determine the microstructure design variables. The training criteria of the supervised learning process include both microstructure correlation functions and material properties. The proposed methodology effectively reduces the infinite dimension of the microstructure design space to a small set of descriptors without a significant information loss. The benefits are demonstrated by an example of polymer nanocomposites optimization. We compare designs using key microstructure descriptors versus using empirically chosen microstructure descriptors as a demonstration of the proposed method.