Boron (B) powder with a high-energy density can enhance the energy of propellants. It has two different forms, namely amorphous B and crystalline B, which have different behaviors during the oxidation. Especially, the oxidation layer (OL) on its surface inhibits the ignition and combustion (IC). To comprehend the formation of OL on the amorphous B nanocluster (BNC) and elucidate its oxidation mechanism, the investigation was conducted on the oxidation of amorphous BNC at various oxygen contents and temperatures (300–1900 K). An analysis of the initial oxidation products (OP), the formation process of the oxidation layer, the reaction path, and the oxidation rate were encompassed and the microscopic oxidation mechanism that cannot be observed experimentally was revealed. The morphology of B (crystalline or amorphous B) does not significantly affect the OP and the thickness of OL. The initial OP of amorphous BNC are BO2 rather than B2O3, and the ultimate OP consist of BO2, BO, and polymer BmOn (m≠1). The oxidation layer on the B surface exhibits a relatively thin thickness. The oxidation rates of two different types of B both follow a parabolic law. The atomic structure of B cluster has an important influence on the reactivity of B. The oxidation rate is influenced by both the surface structure and the oxygen content of amorphous BNC. Based on the above research, a novel oxidation mechanism of amorphous BNC was proposed.