Abstract: Artemisia annua L. (A. annua) has long been documented in traditional Chinese medicine for managing hemorrhagic conditions, attributed to its cooling and hemostatic properties. These historical applications suggest a potential role of A. annua in platelet-related disorders, although its hematopoietic mechanisms remain unclear. To investigate the thrombopoietic activity of A. annua, identify its bioactive constituent, and elucidate the molecular mechanisms underlying its effects on thrombopoiesis. Chemical profiling identified major compounds in A. annua. MK differentiation was assessed in K562, Meg-01 cells, and primary murine haematopoietic stem and progenitor cells (HSPCs). A murine radiation-induced thrombocytopenia (RIT) model was used to evaluate in vivo efficacy. Molecular docking, drug affinity responsive target stability (DARTS), and signaling assays were conducted to explore molecular mechanisms. A. annua promoted MK differentiation, upregulating CD41/CD42b and enhancing polyploidization. Artemisinin was identified as the principal active compound. It promoted MK maturation in vitro and restored platelet counts, MK numbers, and HSPC populations in RIT mice without inducing systemic toxicity. Artemisinin also reduced bone marrow (BM) apoptosis and DNA damage while restoring platelet function. Mechanistically, artemisinin directly bound to FLT3 and activated the FLT3/MAPK pathway, leading to increased phosphorylation of MEK/ERK and upregulation of NF-E2 and TAL1. FLT3 and ERK inhibition abrogated these effects. Artemisinin is a potent thrombopoietic agent that acts via direct activation of FLT3 and its downstream MAPK signaling cascade. The findings identify FLT3 as a novel therapeutic target for thrombocytopenia and support the potential clinical application of artemisinin in radiation-related hematological disorders.