Li-Xia-river Wetlands make up the biggest freshwater marsh in East China. Over the last decades, social and economic developments have dramatically altered the natural wetlands landscape. Mitigating land use conflict is beneficial to protect wetlands, maintain ecosystem services, and coordinate local socioeconomic development. This study employed multi-source data and GIS-based approaches to construct a composite index model with the purpose of quantitatively evaluating the intensity of land use conflict in Li-Xia-river Wetlands from 1978 to 2018. The results showed that the percentage of the wetlands’ area declined from 20.3% to 15.6%, with an overall reduction rate of 23.2%. The mean index of land use conflict increased from 0.15 to 0.35, which suggests that the conflict intensity changed from “no conflict” to “mild conflict.” The number of severe conflict units increased by about 25 times. A conspicuous spatial variation of land use conflict was observed across different periods, although taking land for agricultural activities was the overriding reason for wetlands reduction. However, in recent years, urban sprawl has posed the greatest threat to Li-Xia-river Wetlands. Coordinating land use conflict and formulating a practical strategy are the initial imperative steps to mitigate the threat to wetlands.