Simulating flow dynamics in large-scale lakes is often time-consuming. For river flood simulation, the automatic domain updating (ADU), which can effectively control the simulation domain only in and around the flooded areas, has recently been developed. It is easily implementable without any computational errors for river flood simulation; however, its applicability to lake flow simulation with precipitation/evapotranspiration has not been investigated. This study examines the applicability of the ADU to large-scale lake flow simulation with the 2-dimensional local inertial equations (2D-LIE) taking the Tonle Sap Lake, Cambodia, as a study site. The 2D-LIE with the ADU demonstrated 2.1 times faster simulation with errors less than 5.5%. This efficiency was achieved owing to the wet/dry seasonal nature of the tropical lake and backflow from the mainstream of the Mekong River in the rainy season, suggesting that the ADU is applicable to large-scale lake flow simulation.