Despite recent breakthroughs in understanding how protein sequence relates to structure and function, considerably less attention has been paid to the general features of protein surfaces beyond those regions involved in binding and catalysis. This article provides a systematic survey of the universe of protein surfaces and quantifies the sizes, shapes, and curvatures of the positively/negatively charged and hydrophobic/hydrophilic surface patches as well as correlations between such patches. It then compares these statistics with the metrics characterizing nanoparticles functionalized with ligands terminated with positively and negatively charged ligands. These particles are of particular interest because they are also surface patchy and have been shown to exhibit both antibiotic and anticancer activities-via selective interactions against various cellular structures-prompting loose analogies to proteins. The analyses support such analogies in several respects (e.g., patterns of charged protrusions and hydrophobic niches similar to those observed in proteins), although there are also significant differences. Looking forward, this work provides a blueprint for the rational design of synthetic nano-objects with further enhanced mimicry of proteins' surface properties. Protein surfaces dictate how they interact with thousands of other molecules in the crowded milieu of the cell. Although most attention is given to specific functional interactions, proteins must also evolve to avoid nonfunctional interactions. By exhaustively surveying the statistics of chemical and geometric features of proteins, general principles for designing protein-mimetic nanoparticles are proposed.image (c) 2024 WILEY-VCH GmbH