Aim To study the effects of melatonin (MT) on homocysteine (Hcy)-induced injury of coronary artery endothelial cells and clarify whether the mechanism is related to the activation of protein kinase B (Akt)/mammalian rapamycin target protein (mTOR) pathway. Methods Human coronary artery endothelial cells (HCAEC) were cultured and grouped. The control group was treated with DMEM without drugs, the Hcy group with DMEM containing 1 mmol/L Hcy, the MT group with DMEM containing 1 mmol/L Hcy and 5 μmol/L MT, and the MT+LY group with DMEM containing 1 mmol/L Hcy, 5 μmol/L MT and 10 μmol/L LY2942. Cell viability, cell apoptosis, cell cycle and the expression of p-Akt and p-mTOR were detected. Results Cell viability,Sü phase and G2/M phase ratio, the expression of Bcl-2, cyclinD1, p-Akt and p-mTOR in Hcy group were lower than those in control group, apoptotic rate, G0/G1 phase ratio, the expression levels of Bax and cleaved caspase-3 in Hcy group were higher than those in control group; cell viability,Sü phase and G2/M phase ratio, the expression levels of Bcl-2, cyclinD1, p-Akt and p-mTOR in MT group were higher than those in Hcy group, apoptotic rate, G0/G1 phase ratio, the expression levels of Bax and cleaved caspase-3 in MT group were lower than those in Hcy group; cell viability,Sü phase and G2/M phase ratio, the expression of Bcl-2, cyclinD1, p-Akt and p-mTOR in MT+LY group were lower than those in MT group, apoptotic rate, G0/G1 phase ratio, the expression levels of Bax and cleaved caspase-3 in MT+LY group were higher than those in MT group. Conclusion MT can reduce the apoptosis of HCAEC induced by Hcy, regulating Akt/mTOR pathway is one of the mechanisms responsible for MT reducing HCAEC injury.