Nature has exploited medium-sized 8- to 11-membered rings in a variety of natural products to address diverse and challenging biological targets. However, owing to the limitations of conventional cyclization-based approaches to medium-ring synthesis, these structures remain severely underrepresented in current probe and drug discovery efforts. To address this problem, we have established an alternative, biomimetic ring expansion approach to the diversity-oriented synthesis of medium-ring libraries. Oxidative dearomatization of bicyclic phenols affords polycyclic cyclohexadienones that undergo efficient ring expansion to form benzannulated medium-ring scaffolds found in natural products. The ring expansion reaction can be induced using three complementary reagents that avoid competing dienone-phenol rearrangements and is driven by rearomatization of a phenol ring adjacent to the scissile bond. Cheminformatic analysis of the resulting first-generation library confirms that these molecules occupy chemical space overlapping with medium-ring natural products and distinct from that of synthetic drugs and drug-like libraries.