[Objective] The temporal and spatial evolution of landscape ecological risk, driving forces, and their correlation with the spatial distribution of the COVID-19 epidemic were studied, in order to provide a theoretical reference for regional ecological environment protection, sustainable development, and epidemic control. [Methods] Landsat remote sensing images of Ruili City in Yunnan Province were used to extract landscape type distribution data in 2000, 2010, 2015, and 2021 by using methods such as landscape artificial disturbance intensity, an ecological risk assessment model, and the GWR model. The temporal and spatial changes of the landscape types and ecological risks in Ruili City from 2000 to 2021 were quantitatively studied. The relationships between landscape artificial disturbance intensity and landscape ecological risks, and the spatial distribution of the COVID-19 epidemic were determined. [Results] ① From 2000 to 2021, landscape types of Ruili City were mainly woodland and garden land. Forest and garden areas were relatively stable, while the area of arable land fluctuated, and the construction land area continued to expand; ② From 2000 to 2021, the intensity of landscape artificial disturbance in Ruili City was mainly low, slowly increasing outwards in a dotted pattern. The overall trend was expansion from the northwest to the southeast direction. The area of medium and high intensity areas continued to increase, and the intensity of the southern area along the Ruili River gradually deepened; ③ Landscape ecological risk level of Ruili City was classified as lower-risk and low-risk areas, and shifted from low-level to high-level over time. The low-risk areas were mainly located in the middle of the study area, and the medium-risk and high-risk areas were mainly located in the northwest and southeast areas. Landscape ecological risks in different periods were spatially clustered in high-high and low-low level, with strong autocorrelation; ④ The spatial distribution of the COVID-19 epidemic in Ruili City in 2021 presented the clustering characteristics of one main center and two secondary centers. The spatial distribution of the epidemic was correlated with the landscape ecological risk index and the intensity of landscape artificial disturbance. [Conclusion] During the study period, the landscape types of Ruili City changed significantly, the ecological risk increased, and the ecological environment showed a trend of deterioration. The change of landscape type in Ruili City was obvious, the ecological risk increased, and the ecological environment deteriorated. The spatial distribution of the COVID-19 epidemic was correlated with the landscape pattern. Urban construction land and ecological land had spatial aggregation and obstruction effects on the spread of the virus.