Ball mill grinding circuits are essentially multi-variable systems characterized with couplings, time-varying parameters and time delays. The control schemes in previous literatures, including detuned multi-loop PID control, model predictive control (MPC), robust control, adaptive control, and so on, demonstrate limited abilities in control ball mill grinding process in the presence of strong disturbances. The reason is that they do not handle the disturbances directly by controller design. To this end, a disturbance observer based multi-variable control (DOMC) scheme is developed to control a two-input-two-output ball mill grinding circuit. The systems considered here are with lumped disturbances which include external disturbances, such as the variations of ore hardness and feed particle size, and internal disturbances, such as model mismatches and coupling effects. The proposed control scheme consists of two compound controllers, one for the loop of product particle size and the other for the loop of circulating load. Each controller includes a PI feedback part and a feed-forward compensation part for the disturbances by using a disturbance observer (DOB). A rigorous analysis is also given to show the reason why the DOB can effectively suppress the disturbances. Performance of the proposed scheme is compared with those of the MPC and multi-loop PI schemes in the cases of model mismatches and strong external disturbances, respectively. The simulation results demonstrate that the proposed method has a better disturbance rejection property than those of the MPC and PI methods in controlling ball mill grinding circuits.