Glucocorticoid use is the main cause of secondary osteoporosis. This study aimed to assess the potential protective effects of tocotrienols (T) and CoQ10(C), singly and in combination, against dexamethasone (DEX)-induced osteoporosis in rats and their possible mechanisms. Thirty adult male albino rats were divided into five groups: control group (CON), DEX-treated group received DEX (2.5 mg/kg) intramuscularly twice weekly. The DEX+C, DEX+T, and DEX+TC groups received DEX with T (60 mg/kg), C (20 mg/kg) daily, and their combination respectively, daily orally for 8 weeks. Results revealed that T, C and TC ameliorated DEX-induced osteoporosis through improved osteocalcin (OC), alkaline phosphatase (ALP), Ca and TAC serum levels. Restoration of the expression levels of Nrf2, LC3, and Bcl-2 and improved histological structure of the bones were observed. The combination of the drugs was more effective than each single agent. Both drugs might be promising agents as prophylaxis against osteoporosis via suppressing oxidative stress and apoptosis and enhancing autophagy.