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Stress and illness connection is complex and involves multiple physiological systems. Panax ginsengs, reputed for their broad-spectrum “cure-all” effect, are widely prescribed to treat stress and related illnesses. However, the identity of ginseng's “cure-all” medicinal compounds that relieve stress remains unresolved. Here, we identify ginsentides as the principal bioactives that coordinate multiple systems to restore homeostasis in response to stress. Ginsentides are disulfide-rich, cell-penetrating and proteolytic-stable microproteins. Using affinity-enrichment mass spectrometry target identification together with in vitro, ex vivo and in vivo validations, we show that highly purified or synthetic ginsentides promote vasorelaxation by producing nitric oxide through endothelial cells via intracellular PI3K/Akt signaling pathway, alleviate α1-adrenergic receptor overactivity by reversing phenylephrine-induced constriction of …