Objective: To investigate the bone-protective potential of Nelumbo nucifera Gaertn. seed hydroalcoholic extract (NNHE) in an ovariectomized (OVX) rat model by modulating the estrogen receptor/osteoprotegerin/receptor activator of nuclear factor (NF)-κB (ER/OPG/RANKL) signaling pathway. Methods: Network pharmacology was employed with the databases of PubChem, BindingDB, DisGeNET, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG), along with Cytoscape 3.10.2 for identifying the targets and pathways of NNHE relevant to OP. A total of 48 specific pathogen-free (SPF) grade female Wistar rats were randomly divided into six groups (n = 8 per group): sham control, OVX control, OVX + NNHE [100, 200, 400 mg/(kg·d)], and OVX + alendronate [3 mg/(kg·week)]. The treatment lasted for 16 weeks. Post-treatment assessment included bone parameters (weight, thickness, density, volume, and length), serum biochemical markers [parathyroid hormone (PTH), estrogen, OPG, RANKL, tartrate-resistant acid phosphatase (TRAP), osteocalcin (OC), calcitonin (CT), calcium (Ca), phosphorus (P), and alkaline phosphatase (ALP)], pro-inflammatory cytokines [tumour necrosis factor (TNF)-α, NF-κB, interleukin (IL)-1β, and IL-6], lipid profiles [total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL), and high density lipoprotein (HDL)], oxidative stress markers [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH), and malondialdehyde (MDA)], and histopathological analyses of femur, uterus, and vaginal tissues. Results: Network pharmacology analysis revealed 61 overlapping targets between NNHE and osteoporosis-related genes, including signal transducer and activator of transcription 3 (STAT3), NF-κB subunit 1 (NFKB1), dopamine receptor D2 (DRD2), matrix metalloproteinase 9 (MMP9), and caspase-3. GO and KEGG enrichment suggested involvement in the ER/OPG/RANKL signaling pathway. In vivo studies demonstrated that NNHE treatment (400 mg/kg) significantly reduced OVX-induced body weight gain and exhibited estrogenic activity in the vaginal cornification assay. NNHE at 200 and 400 mg/kg significantly increased serum estrogen levels compared with OVX control group, while uterine weight remained unaffected. NNHE significantly improved the lipid profile compared with OVX group, with TC, TG, and LDL decreased, while HDL levels were increased at 200 and 400 mg/kg. Bone metabolism markers were significantly improved compared with OVX group, with serum Ca and P levels restored at all NNHE doses and ALP activity reduced. NNHE effectively modulated bone turnover markers compared with OVX group by reducing levels of OC, TRAP, and PTH, and increasing level of CT. In addition, NNHE decreased RANKL level while increasing OPG level at 200 and 400 mg/kg. Bone mineral density (BMD) was significantly enhanced compared with OVX group. Serum oxidative stress was significantly mitigated compared with OVX group through increased levels of antioxidant enzymes (SOD, CAT, and GSH) and reduced MDA, with the most pronounced effects observed at 400 mg/kg. Pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, and NF-κB) were significantly reduced in all NNHE treatment groups compared with OVX group. Histopathological analysis confirmed restoration of trabecular bone structure and normalization of reproductive tissue morphology in OVX rats after NNHE treatment. Conclusion NNHE demonstrated significant protective effects against OVX-induced osteoporosis through ER/OPG/RANKL signaling pathway modulation, oxidative stress, and inflammation suppression, resulting in improved BMD and structural integrity. These findings indicate that NNHE may represent a promising therapeutic candidate for postmenopausal osteoporosis management and merits further clinical investigation.