SignificanceCurrent efforts aimed at constructing complex supramolecular structures often suffer from low yields or require long assembly protocols. We address these problems by demonstrating a facile strategy for optimizing the nucleation step of a multicomponent self-assembly reaction. By tracking the formation of multisubunit clusters in situ, our experiments show that modifying the critical nucleus required to initiate structure growth can broaden the range of conditions over which self-assembly occurs and, consequently, can dramatically improve the final yield of correctly formed structures. Since varying the design of only a small portion of the target structure optimizes its yield, this strategy provides a practical route to improve the speed and accuracy of self-assembly in biomolecular, colloidal, and nanoparticle systems.