Aiming at the optimal layout of a deep chamber for coal−gangue separation (DCCS) based on the weak stratum horizon, an in-depth study was carried out by combining field investigations, model tests, and numerical simulations. Firstly, the main structural characteristics of DCCS were summarized. Then, the deformation and failure law for rocks surrounding DCCS were revealed under different horizons in the weak stratum. Finally, the optimal layout methods of DCCS based on the thickness and horizon in the weak stratum were determined in different in situ stresses, using the proposed comprehensive evaluation method for surrounding-rock stability. The results show that if the thickness of the weak stratum was small, the side near the roof of DCCS should be arranged along the weak stratum when the lateral pressure coefficient was λ < 0.6 or λ > 1. The side near the floor of DCCS was arranged along the weak stratum when 0.6 ≤ λ ≤ 1 and the surrounding-rock stability was the best. If the thickness of the weak stratum was large, the side of DCCS should be arranged along the weak stratum when λ < 0.6 or λ > 1. The floor of DCCS was arranged along the weak stratum when 0.6 ≤ λ ≤ 1, which was most favorable for the surrounding-rock control. The research results have important guiding significance for the spatial layout and support design of DCCS.