Scenario simulation and loss prediction of flood disasters are of great significance for flood control and disaster reduction in lake basins. Therefore, Nansi Lake Basin, a typical lake basin in China, was taken as an example for study. We used CA-Markov model to simulate three land use scenarios in 2030, and used P-III probability curve to construct 10-, 20-, 50- and 100-years recurrence periods of heavy rainfall. Then, 12 climate and land use change combination scenarios were built. Runoff and submergence depth in different scenarios were quantified by InVEST model and equal volume submergence method. Combined with GDP spatial forecast data, the direct economic losses of flood under 12 scenarios were calculated. The results showed that: (1) simulation accuracy of land use by CA-Markov model in Nansi Lake Basin was high, and land use changes in each scenario were significant. (2) The impact of land use change on flood disaster was significant. The urban development scenario had the highest risk of flood disasters, while the ecological protection scenario had the lowest risk. (3) The enhanced rainstorm would significantly increase the economic loss of each land use scenario, but the increments would slow down after the 50-year recurrence period. The total economic loss of the ecological protection scenario was the least, ranging from 9.739 billion to 12.881 billion RMB. Compared to other land use scenarios, this scenario had the effect of reducing disaster losses. Therefore, the sustainable development of lake basins should be based on the impact of land use changes on flood disaster risks in the context of climate change. In the future, the reasonable expansion of urban construction land should be considered, ecological land layout should be optimized, and the role of territorial spatial planning in flood control and disaster reduction should be fully utilized.