One of the most critical aspects of mine design is to determine the optimum cut-off grade. Despite Lane’s theory, which aims to optimize the cut-off grade by maximizing the net present value (NPV), which is now an accepted principle used in open pit planning studies, it is less developed and applied in optimizing the cut-off grade for underground polymetallic mines than open pit mines, as optimization in underground polymetallic mines is more difficult. Since there is a similar potential for optimization between open pit mines and underground mines, this paper extends the utilization of Lane’s theory and proposes an optimization model of the cut-off grade applied to combined mining-mineral processing in underground mines with multi-metals. With the help of 3D visualization model of deposits and using the equivalent factors, the objective function is expressed as one variable function of the cut-off grade. Then, the curves of increment in present value versus the cut-off grade concerning different constraints of production capacities are constructed respectively, and the reasonable cut-off grade corresponding to each constraint is calculated by using the golden section search method. The defined criterion for the global optimization of the cut-off grade is determined by maximizing the overall marginal economics. An underground polymetallic copper deposit in Tibet is taken as an example to validate the proposed model in the case study. The results show that the overall optimum equivalent cut-off grade, 0.28%, improves NPV by RMB 170.2 million in comparison with the cut-off grade policy currently used. Thus, the application of the optimization model is conducive to achieving more satisfactory economic benefits under the premise of the rational utilization of mineral resources.