Ligustrazine has gained significant attention for its unique structural role in natural medicinal chemistry and its potential in drug discovery and development. The ligustrazine structure has been recognized as a clinical drug for treating cardiovascular and cerebrovascular diseases, especially in the design of neuroprotective agents. Recently, ligustrazine-based anti-tumor agents have also been reported. This knowledge can undoubtedly be applied to design multi-target-directed ligands, a highly relevant strategy for the complex pathological conditions of multifactorial diseases. In this review, we first discuss the biological properties and clinical applications of ligustrazine, then focus on the rational design of ligustrazine-based multifunctional ligands.