Northwest China is a key area of China’s Western Development Project and the core coverage area of the Belt and Road Initiative. It is also an important area for maintaining China’s national defense and ecological, social, economic, and cultural security. In the new era, improving the input-output efficiency of the social economy as well as the resources and environment in northwest China is an important route to advance the construction of an ecological civilization, promote high-quality transformation development, and guarantee the long-term stability of the country. Therefore, we here constructed a comprehensive index system for measuring the input-output efficiency and used the ME-DEA model and the Mann-Kendall trend test and spatial variability coefficient to analyze the spatiotemporal changes. The results demonstrated the following: (1) The overall input-output efficiency in northwest China fluctuated from 0.883 in 2000 to 0.975 in 2017, hovering within a range of low efficiency the entire time. There was no general improvement trend, with only 43.33% of the prefecture-level regions exhibiting significant improvement. (2) The socioeconomic efficiency in northwest China fluctuated from 0.984 in 2000 to 1.079 in 2017, shifting from a low to a medium level. Though it exhibited a trend of improvement overall, only 40.00% of the prefecture-level regions exhibited significant improvement. (3) The resources and environmental efficiency in northwest China fluctuated from 0.807 in 2000 to 0.897 in 2017, hovering at a low level the entire time and showing little improvement. Only 31.67% of the prefecture-level regions showed significant improvement. (4) The overall input-output efficiency in northwest China exhibited a pattern including a widespread distribution of low and medium efficiency and sporadic distribution of medium-high and high efficiency. The socioeconomic efficiency evolved from a widespread distribution of low efficiency to a basically balanced distribution of all types. The resource and environmental efficiency exhibited a pattern of absolute dominance of low and medium efficiency and the occasional occurrence of medium-high and high efficiency. The above results showed that promoting the input-output efficiency from a low to a high level is an important task for all levels of government in northwest China. Furthermore, a benign interactive coupling mechanism between the social economy and the eco-environment should be established, and making up for the shortcomings of resource and environmental efficiency should be set as a top priority. Specific measures include promoting the transformation of the industrial structure from being resource-intensive to technology-intensive, improving resource use efficiency, and reducing the environmental pollution level as well as gradually getting rid of the strong dependence of socioeconomic development on resource inputs.