Glucocorticoids (GCs) are the most prescribed anti-inflammatory and immunosuppressive drugs. However, their use is often limited by substantial side effects, such as GC-induced osteoporosis (GIO) with the underlying mechanisms still not fully understood. In this study, we identify Tau as a low-affinity binding receptor for GCs that plays a crucial role in GIO. Tau deficiency largely abolished bone loss induced by high-dose dexamethasone, a synthetic GC, in both inflammatory arthritis and GIO models. Furthermore, TRx0237, a Tau inhibitor identified from an FDA-approved drug library, effectively prevented GIO. Notably, combinatorial administration of TRx0237 and dexamethasone completely overcame the osteoporosis adverse effect of dexamethasone in treating inflammatory arthritis. These findings present Tau as a previously unrecognized GC receptor with low affinity, and provide potential strategies to mitigate a spectrum of GC-related adverse effects, particularly osteoporosis.