The Mannich reaction has been widely used to effectively construct C–N and C–C bonds in organic synthesis. This review focuses on selected applications of the intramolecular Mannich reaction as a key step in the total synthesis of natural products (2000–2017). The organization of the synthetic applications is based on the structure of newly-formed skeletons using the intramolecular Mannich reaction, which include aza-fused rings and aza-bridged rings.