Multiseam interactions are a major source of ground and pillar instability in many underground coal mines. The objective of this study is to propose a method for determining the optimal parameters of a panel layout for the room-and-pillar retreat mining with the rational extraction ratio and stability factor of pillar in multiple coal seams. First, key factors to ensure high extraction ratio and pillar stability in room-and-pillar retreat mining are selected as four parameters, and their value range and levels are determined according to geological and mining conditions, previous experiences. Then, the numerical analysis for the stability of the pillar system in the retreat mining panel was implemented by the Analysis of Multiple Seam Stability (AMSS) software in combination with an orthogonal experimental table, and the influence of each factor on the extraction ratio and stability factor of pillar is evaluated. Finally, it was found that the effect of the number of entries on the recovery rate and pillar stability factor was the largest regardless of the undermining or overmining, and the extraction ratio and pillar stability factor in the optimal mining panel with 8 of number of entries, 1.5 m of entry height, 7 m of entry width and 20 m of crosscut spacing are 69.2% and 1.87, respectively.