This study aims to explore the mechanism and key targets of the "homotherapy for heteropathy" of Eucommia ulmoides Oliv. in the treatment of osteoporosis (OP) and Alzheimer’s disease (AD). The potential targets of E. ulmoides in treating AD and OP were screened through databases such as TCMSP. GO and KEGG enrichment analyses were performed on the core targets. The STRING database was utilized to construct protein-protein interaction (PPI) networks, and the core modules and hub genes in the PPI network were detected. Molecular docking was employed to simulate the binding ability of the active ingredients of E. ulmoides with the key targets. Furthermore, an ovariectomy (OVX) animal model with two phenotypes of OP and AD was established. Behavioral assays, hematoxylin-eosin (HE) staining, enzyme-linked immunosorbent assay (ELISA), and Western blot (WB) techniques were employed to validate the crucial therapeutic effects of E. ulmoides on AD and OP. A total of 17 active ingredients of E. ulmoides were obtained from the database, and 63 targets for the "homotherapy for heteropathy" were identified, which were involved in biological processes such as steroid metabolic processes and signaling pathways like estrogen and mitogen-activated protein kinase (MAPK). Through PPI analysis, it was found that interleukin-6 (IL-6), tumor necrosis factor (TNF), estrogen receptor α (estrogen receptor 1, ERα), prostaglandin-endoperoxide synthase 2 (PTGS2), and interleukin-1β (IL-1β) were the key targets of the active ingredients of E. ulmoides, all of which were enriched in the MAPK signaling pathway. The results of molecular docking demonstrated that the active ingredients of E. ulmoides had a good binding affinity with ERα. Animal experiments indicated that E. ulmoides could alleviate the symptoms of AD and OP in OVX model mice, such as cognitive impairment, destruction of trabecular bone structure, and increased bone metabolism. Moreover, E. ulmoides also reduced the contents of IL-1β, IL-6, and TNF-α in bone and brain tissues and decreased the expression level of phospho extracellular regulated protein kinases 1/2 (pERK1/2). After the administration of ERα blockers, the therapeutic effects of E. ulmoides were reversed. E. ulmoides may play a crucial role in the treatment of OP and AD by regulating the MAPK/ERK pathway via the ERα receptor, thereby providing experimental and theoretical references for the "homotherapy for heteropathy" of E. ulmoides in the treatment of OP and AD.