The flocculation effect of Hx-600 on the simulated red mud of the Bayer Process from diaspore with high levels of silicon and iron was investigated, and a flocculant with high content of hydroxamate groups (HCPAM) and sodium polyacrylate (PAAS) was chosen as the model compound of Hx-600. The typical silicon containing and iron containing monominerals in red mud, hydration grossular and hematite, were correspondingly synthesized, and the adsorption mechanism with HCPAM or PAAS was investigated using FTIR and XPS, respectively. The results reveal physical adsorption of HCPAM or PAAS on the surfaces of hydration grossular and chemisorption of HCPAM or PAAS on the surfaces of hematite. The atomic Mulliken populations of the model compounds of HCPAM and PAAS were calculated by quantum chemical calculation. The results show that a five-membered ring may be formed on the surfaces of HCPAM-treated hematite and a four-membered ring may be formed on the surfaces of PARS treated hematite. A stronger adsorption of the flocculant with hydroxamate groups on the hematite surfaces can be estimated, compared to carboxyl groups. Therefore, the improvement of settling performance achieved by Hx-600 could be attributed to the high content of hydroxamate groups and high molecular weight (mass) of Hx-600. A chemisorption with a bridging flocculation between the iron-containing component in red mud and Hx-600, and a physical adsorption with a bridging flocculation between the silicon-containing component in red mud and Hx-600 can enhance the settling performance of the simulated red mud of the Bayer process from diaspore with thigh levels of silicon and iron.