Background and Purpose: Adenomyosis causes pain, abnormal bleeding, and infertility. Epithelial-mesenchymal transition (EMT) plays a critical role in the pathogenesis of adenomyosis. Current therapies are mainly hormone-dependent and their termination led to aggravations. To develop novel pharmacological treatment is necessary. Safflower was widely used to treat gynecological disease in China, the effect of hydroxysafflower yellow A (HSYA) that is the major active component of Safflower on adenomyosis remains unclear. We investigated whether HSYA ameliorates adenomyosis, and further revealed its potential target and mechanisms. Experimental Approach: Adenomyosis was induced in female ICR mice by oral administration of tamoxifen on days 2-5 after birth. At the 16th week, HSYA were administrated for 3 weeks. Adenomyosis development, autophagy activity, and involved mechanisms were analyzed using HE and Masson staining, western blotting, immunofluorescence, and RNA-sequencing. Furthermore, network pharmacology and molecular docking were applied to assess the potential target of HSYA. Key Results: HSYA ameliorates adenomyosis via promoting autophagy and ameliorating the activation of PI3K-AKT-mTOR. Isocitrate dehydrogenase1(IDH1) was found to be the potential target of HSYA. After IDH1 was knocked down by si-RNA, autophagy was activated, and EMT was attenuated via inhibiting PI3K-AKT-mTOR by HSYA. Conclusions and Implications: HSYA significantly ameliorates adenomyosis, and IDH1-autophagy-EMT plays an important role in the progress of adenomyosis. It will shed new light on a potential novel therapeutic strategy for adenomyosis.