To investigate the collaborative optimization problem of blasting effect and drilling and blasting cost under complex working conditions in plateau open-pit mines, an integrated optimization method for hole network parameters combining multi-objective evaluation and numerical simulation verification based on the TOPSIS method was proposed. Based on the actual working conditions of a super-large plateau open-pit mine, the value ranges and comparison schemes of hole network parameters were determined in combination with parameters such as bench height and bench slope angle. Taking blasting effect and drilling and blasting cost as evaluation indexes, the predicted values of evaluation indicators for each comparison scheme were calculated by using the Kuz-Ram blasting fragmentation model and the drilling and blasting cost model. The TOPSIS method was employed to conduct a comprehensive evaluation and ranking optimization of each comparison scheme. Blasting damage numerical simulations for the comparison schemes were performed using the Ansys LS-DYNA software. The results show that the comprehensive scoring ranking of the five schemes is as follows: Scheme 3 (0.559) > Scheme 2 (0.544) > Scheme 4 (0.528) > Scheme 1 (0.507) > Scheme 5 (0.493), indicating that Scheme 3 achieves the highest comprehensive score. In the blasting damage nephogram of the optimal Scheme 3 (hole spacing of 10 m × row spacing of 8.5 m), the strongly fragmented zone, the fracture development zone, and the weakly damaged zone are evenly distributed. The blasting damage range achieves a relatively balanced control between effective fragmentation and excessive damage, thereby realizing an optimized balance between blasting effect and drilling and blasting cost. The research results can provide a reference for the optimization of blasting hole network parameters in open-pit mines.