Mineral grinding circuit (GC) is essentially multivariable system characterized with strong couplings, large time-varying parameters and multiple time delays. The product particle size and the circulating load are two important production indexes that directly related to the operation performances of subsequent beneficiation process. However, they are usually difficult to be controlled effectively with conventional control strategies due to the above mentioned complex characteristics. Especially the various process disturbances have a great influence on the control performances of the closed-loop system. In this paper, a multivariable disturbance observer (MDOB) based analytical non-interacting control (ANC) scheme is proposed to control the complex GC with model mismatches and strong external disturbances. Control studies have been performed by simulation tests for setpoint tracking, disturbance rejection and robustness problems.