Huperzine A is an alkaloid featuring a bicyclo [3.3.1] nonane scaffold with an integrated piperidine ring, which was firstly isolated from Huperzia selago in 1960. As a reversible acetylcholinesterase inhibitor, it was clinically approved in China for treatment of Alzheimer's disease in 1996. Although huperzine A shows therapeutic potential, it is often associated with adverse events, such as dizziness, nausea, and digestive disorders. To enhance the efficacy and therapeutic index of huperzine A, many structural modification efforts have been undertaken. This review comprehensively summarizes the structural modification investigations on huperzine A conducted over the past three decades, and the structure-activity relationships are also discussed. The insights from this review are expected to inspire more effective modification strategies in the future.