Eco-efficiency is the comprehensive embodiment of regional development quality, and the synthetic reflection of coordination degree between socio-economic system and environmental system. Taking the Yellow River Basin as the research area, this study explored the spatio-temporal evolution and driving forces of eco-efficiency of resource-based cities. At first, eco-efficiencies of 37 resource-based cities from 2003 to 2017 were evaluated, using the TOPSIS method. Then, the spatio-temporal changing trends were revealed through the Theil index, the Global Spatial Autocorrelation analysis and the Hotspot analysis. At last, the key driving factors of eco-efficiency change were explored by the Panel Tobit Regression model. The results showed that: (1) On the whole, the eco-efficiency of resource-based cities in the Yellow River Basin stabilized first and then increased during 2003 and 2017, with 2007 as the turning point. However, the quantity and rate of eco-efficiency growth varied considerably among resource-based cities. The two indexes of downstream cities were significantly higher than those of middle and upstream cities, and these two indexes of regenerative cities were significantly higher than those of growing cities, grow-up cities and recessionary cities. (2) The eco-efficiency gap between resource-based cities decreased slightly at first and then increased continuously during 2003 and 2017. Meanwhile, the eco-efficiency spatial distribution pattern of resource-based cities evolved from random state to aggregate state. Specifically, the low-value agglomeration areas were distributed at the junction of Shanxi and Henan provinces at first, and then moved upstream to the central and northern parts of Shanxi province. The high-value agglomeration areas, however, remained consistently in Shandong province, which is located in the lower reaches of the Yellow River. (3) In general, industrial transformation, scientific and technological innovation, infrastructure improvement and location conditions had significant positive effects on the improvement of eco-efficiency in the study area. However, export-oriented economy, resource dependence and environmental regulation had significant inhibitory effects, and urbanization, industrialization and foreign capital utilization had no significant impact. It is worth noting that the driving factors of eco-efficiency were heterogeneous across different types of resource-based cities, which means that different resource-based cites should take different measures to improve their eco-efficiencies.