Epidemiological studies have reported varying associations between coffee consumption and bone mineral density. This study aims to systematically asses the pharmacological effects of prolonged coffee intake on osteoblasts, osteoclasts, and postmenopausal osteoporosis induced by ovariectomy. In vitro, experiments revealed that coffee water extract upregulated the expression of osteogenic-related proteins such as 12.5 μg/mL middle concentration group had a 1.33 fold increase in collagen type Ⅰ α 1 (COL1A1) expression, and a 1.83 fold increase in Osterix expression by inhibiting the phosphorylation of protein kinase B (AKT), inhibitor of κB protein-α (IκBɑ), P65, and extracellular signal-regulated kinase (ERK). Additionally, it inhibited receptor activator of nuclear factor kappa B ligand (RANKL)-mediated osteoclastogenesis in RAW264.7 cells though the AKT, MAPKs, and NF-κB pathways, concomitant with the inhibition of nuclear translocation of nuclear factor of activated T cells cytoplasmic 1. In vivo studies demonstrated that a medium-dose coffee sample inhibited osteoclastogenesis, stimulated osteogenesis, and ameliorated bone loss in ovariectomized mice. Molecular docking analysis validated the impact of caffeine, cholorogenic acids, and trigonelline on bone homeostasis. In summary, consumption of 4?5 cups of coffee per day in humans may attenuate ovariectomy (OVX)-associated pathological bone loss by disrupting osteoclast activity and promoting osteogenesis, while long-term consumption of high-dose coffee could disrupt bone homeostasis.