Abstract: It is of great significance to promote green development and harmonious coexistence between humans and nature in order to ensure the safety of water quality in the Project of S-N Water Diversion. The changes in county-level eco-efficiency and their driving factors were explored for the water source area of Middle Route Project of S-N Water Diversion. The non-radial and non-angular super-SBM model were used to calculate the eco-efficiency of 43 counties (districts and cities） in the water source area of Middle Route Project of S-N Water Diversion from 2008 to 2022. The Malmquist Index was used to reveal the internal and external driving factors. The results indicated that the county-level eco-efficiency showed a fluctuating decline from 2008 to 2022. Overall, it was at a moderate to lower level. The trend of county-level eco-efficiency in Shanxi, Hubei, and Henan provinces was generally consistent with the overall trend of the entire region. The overall county-level eco-efficiency showed a distribution pattern of “low in northeast and high in southwest”. The low and high county-level eco-efficiency areas were clustered and connected, while the high and the much lower county-level eco-efficiency areas were relatively scattered. The main reasons for the loss of county-level eco-efficiency included the excessive resource investment and excessive pollutant emissions. The insufficient fiscal fund was also one of the reasons for the loss of county-level eco-efficiency. The PEC Index and the TC index were in a progressive state, but the SEC Index was in a regressive state, which indicated that the improvement of county-level eco-efficiency in the study area was mainly influenced by government macroeconomic regulation and management as well as technological progress. However, the scale economy factors were found to be difficult to play a role in improving county-level eco-efficiency in the water source area of Middle Route Project of S-N Water Diversion.