Rare diseases are largely monogenic in origin; however, they are characterized at the phenotypic level by complex, multi-layered biological network dysfunctions. Although next-generation sequencing technologies have revealed a substantial portion of the genetic basis, a significant translational gap persists from genotype to phenotype and to clinical intervention. This gap arises from the fact that these diseases are shaped not only at the single-gene level but also through integrated disruptions in protein folding, mitochondrial dysfunction, epigenetic dysregulation, and signaling network integrity. In this context, plant metabolites are considered beyond classical pharmacological agents and are redefined as system-level regulators that simultaneously modulate multiple nodes within biological networks. While alkaloids influence the reorganization of signaling networks, terpenoids regulate cellular homeostasis through central signaling pathways such as mechanistic target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT). Phenolic compounds, in turn, exert multi-layered modulation across redox balance, inflammatory responses, and epigenetic regulation axes. Multi-omics integration and artificial intelligence-based modeling approaches enable mechanistic dissection of these complex biological networks and facilitate more precise stratification of disease subtypes. Within this framework, plant metabolites are increasingly being repositioned as key components of network-based precision medicine approaches in rare diseases, functioning as multi-target and system-level modulators.