Mining-induced subsidence is critical for ecological environment reconstruction and damage prevention in coal mining areas. Understanding the characteristics of surface subsidence with multi-seam mining is the first step. Surface subsidence of different mining panel layout configurations was investigated by means of UDEC numerical simulation. Based on the simulation results, it was indicated that mining panel layout configuration had a significant impact on surface subsidence, including ground surface subsidence, horizontal displacement, crack propagation, and ground surface fissure development. The overlapped region of the upper panel and the lower panel is the key region, where existing bedding separations and strata cracks close and activate, the integrity and strength of the interburden layer are reduced, and the subsidence magnitude is enhanced. The subsidence profile of the overlapped region for the stacked configuration, external staggered, the edge of the lower panel internal staggered, two edges of the lower panel internal staggered are steeper and deeper, and the corresponding values of ground surface subsidence and horizontal displacement are greater than other regions. The ground surface fissures with the types of stepped, slided, and graben developed on the ground surface above the edge of the mining panel, and the development location is closely related to the strata movement edge. Because of the support activities of the reserved coal pillar, the ground subsidence of the external staggered (internal staggered) of the upper panel with the coal pillar is slight. The external staggered (internal staggered) and external staggered (internal staggered) of the upper panel with the coal pillar can be selected as the preferred layout configuration. The proposed description of surface subsidence of different mining panel layout configurations can be applied in subsidence prediction.