This article proposes a generic plant-wide control framework that can be used to develop a hierarchical control structure (regulatory control, supervisory control, and optimization) to operate a single-stage closed grinding mill circuit in an economically optimal manner. An economic objective function is defined for the grinding mill circuit with reference to the economic objective of the larger mineral processing plant. A mineral processing plant in this study consists of a comminution and a separation circuit and excludes the extractive metallurgy at a metal refinery. The operational performance of a comminution circuit as represented by a single-stage grinding mill circuit, primarily depends on the performance of the grinding mill. Since grind curves define the operational performance range of a mill, grind curves are used to define the set points for the economic controlled variables for optimal steady-state operation. For a given metal price, processing cost, and transportation cost, the proposed structure can be used to define the optimal operating region of a grinding mill circuit for the best economic return of the mineral processing plant. Once the optimal operating condition is defined, the supervisory control aims to maintain the primary controlled variables at the optimal set points. A regulatory control layer ensures the stability of the plant in the presence of disturbances.