Osteoporosis in post-menopausal women remains one of the most pressing public health challenges worldwide, driven by hormonal changes, aging, and complex interactions between skeletal fragility, sarcopenia, and comorbid conditions. This systematic review synthesizes evidence from 60 studies published across diverse populations to examine epidemiology, diagnostic approaches, therapeutic strategies, and non-pharmacological interventions. Literature searches were conducted using PRISMA 2020 guidelines, and risk of bias was assessed with established Cochrane and GRADE frameworks. The review confirms that the first decade following menopause is a critical period of accelerated bone loss, leading to a surge in vertebral fractures and setting the stage for later hip fractures, which are often associated with 20–30% one-year mortality. Beyond bone mineral density, fracture risk is strongly influenced by sarcopenia, frailty, metabolic disorders such as type 2 diabetes, and secondary osteoporosis from endocrine or renal disease. While dual-energy X-ray absorptiometry remains the diagnostic cornerstone, emerging tools such as vertebral fracture assessment, trabecular bone score, and the FRAX algorithm enhance precision in identifying women at high risk. Therapeutically, bisphosphonates continue to be the most widely studied and prescribed, providing robust and durable fracture protection, while denosumab and anabolic agents such as teriparatide and romosozumab offer newer options for very-high-risk women when used with careful sequencing. Non-pharmacological strategies, including structured exercise, vitamin D and calcium supplementation, falls prevention, and the implementation of Fracture Liaison Services, consistently enhance outcomes and reduce refracture rates. Despite advances, treatment gaps persist globally, with less than one-third of high-risk women receiving appropriate therapy after a fragility fracture, particularly in low- and middle-income countries. This review highlights the urgent need for integrated care pathways, global equity in osteoporosis management, and future research into imminent fracture risk prediction, sarcopenia assessment, and digital health innovations. Taken together, the findings emphasize that effective prevention and treatment of osteoporosis in post-menopausal women demand a holistic approach that combines pharmacological therapy, lifestyle modification, and system-level strategies to reduce the burden of fractures and improve quality of life.