The pathologic phenotype of numerous sporadic and hereditary neurodegenerative disorders is the presence of amyloid deposits the brain. Neurotoxic aggregates of the tau protein have the capacity to spread in a prion-like fashion from diseased to healthy cells causing normal tau to become misfolded. Parallel β-sheet stacking in fibrillar tau is characterized by hydrophobic interactions between sidechains on unique and distant β-strand modules within each protomer. While short aggregation-driving β-strand peptides have been widely employed as models of amyloid propagation, relatively little attention has been paid to the diversity of cross-β modules that interact with these sequences. Recent structural elucidation of tau fibrils isolated from patient-derived extracts also suggests that the conformations of misfolded tau, and the associated intramolecular cross-β interactions, vary by disease. We hypothesized that complete cross-β epitope mimics could serve as strain-selective ligands, synthetic nucleators, or minimalist models of physiologically relevant amyloid folds. Here, we describe a diversity-oriented approach toward peptide macrocycles that feature both the aggregation-prone PHF6 sequence and the cross-β interacting modules observed in solid-state structures of tau. Using a combination of biophysical techniques, we demonstrate that several of our β-arch tau mimics form higher-order assemblies reminiscent of those in pathological states. Moreover, we show that these macrocycles can serve as useful templates for the design of soluble inhibitors of tau aggregation and cellular seeding induced by both full-length recombinant protein and fibrils extracted from patient tissue. Finally, we detail the structure-based design and synthesis of seed-competent proteomimetic macrocycles based on a particularly infective 4R tauopathy fold. More broadly, we anticipate that our novel approach to amyloid mimicry will enable the development of strain-selective ligands, synthetic nucleators, and minimalist models of physiologically relevant amyloid folds.