The intriguing structural complexity and bioactivities of the Daphniphyllum alkaloids have long attracted much attention. Herein, we report the first and enantioselective total synthesis of Daphniphyllum alkaloid dapholdhamine B and its lactone derivative. The chemical structure of dapholdhamine B contains a unique aza-adamantane core skeleton and eight contiguous stereocenters, including three contiguous fully substituted stereocenters, which present a formidable synthetic challenge. This concise approach used to achieve the first synthesis of an azaadamantane natural product features a vinylogous Mannich reaction, an optimized alpha-bromo-alpha,beta-unsaturated ketone synthesis, a substrate-dependent intramolecular aza-Michael addition, a key annulation via amide activation, an S(N)2'-type lactonization, and a facile Horner-Wadsworth-Emmons reaction that converts the hemiacetal moiety to the corresponding homologated carboxylic acid.