To meet the demand of the fast increasing population, enhancing the wheat (Triticum aestivum L.) yield and resource use efficiency by optimizing water and nitrogen (N) management can greatly improve agricultural sustainability and enhance regenerative farming in developing countries such as China. Based on 126 studies conducted in China between 1996 and 2018, using meta-analysis in combination with decision regression tree modeling and life cycle assessment (LCA), this study aimed to (1) quantify the effect of water and N input on wheat yield, water productivity (WPc), and N use efficiency (NUEf), and evaluate the subsequent environmental impact in different regions using LCA; and (2) evaluate, model, and rank the roles of environmental (e.g., soil nutrient status and climatic factors) and agronomic factors (e.g., water and N management practices) affecting wheat yield, WPc, and NUEf. The results showed that irrigation and N addition increased the average yield and WPc by 40 and 15%, respectively, relative to control treatments with no irrigation or fertilizer application. The mean water saving potential (WSP) and N saving potential (NSP) in China were estimated at 11 and 10%, respectively. Soil nutrient status [e.g., initial soil phosphorus (P) and potassium (K)] and soil organic carbon content affected the wheat yield, WPc, and NUEf more significantly than climatic factors [mean annual temperature (MAT)] or water and N management practices. The structural equation-based modeling indicated that initial soil nutrient condition impacted productivity and resource use efficiency more at the below optimal water and N levels than above. The risk-factor-based feature ranking indicated that site-specific environmental and soil condition was highly informative toward model construction but split input of N or water had less impact on yield and input use efficiency. LCA demonstrated that to further mitigate greenhouse gas emissions, water- or N-saving management should be promoted in China. Collectively, our research implies that long-term soil health and nutrient enhancement should be more beneficial for increasing yield and resource use efficiency in wheat production.