Ecosystem deterioration has been and is still a serious threat to human survival and regional economic development. Theoretical and methodological challenges exist in assessing ecological risk of watershed ecosystem that is imposed by natural changes or human activities. To fill this research gap, this research proposes an interdisciplinary and quantitative methodology based on some techniques such as the Procedure for Ecological Tiered Assessment of Risk (PETAR), the Entropy, and the Celluar Automata Markov (CA-Markov). We focused on six vulnerable environmental variables, namely land-use change, water quantity, water quality, gross domestic product (GDP), environmental pollutants, and soil erosion in the Huai River watershed in the Henan Province in order to build multi-dimensional quantitative method. Further, the Coupling Coordination Degree Model is constructed, and the "threshold index" is also addressed to reflect the limitation of ecological risk. Our results show that the spatio-temperal distribution of the eco-environmental quality has greatly varied across this study area during different time spans. Natural eco-environmental quality has moderately degraded in 70% of this study area (mainly agricultural region), at a prefectural level from 2000 to 2010, and has slightly improved over the agricultural region (<170 m above sea level) during 2010-2015. However, when considering negative stressors from human social system on the natural ecosystem, the extent and distribution of the ecological risk varied across the whole area during 2000-2015. The results show that there was almost 90.40% of this region under the ecological risk, with varying extents over the study time, e.g., Kaifeng, Shangqiu, Xuchang, and Xinyang, with a moderate deterioration in the eco-environmental quality, and Zhengzhou with a slight deterioration in the eco-environmental quality. This paper provides a valuable perspective for governments at all levels to manage watershed environment resources.