Substituting mineral fertilizers with manure has been promoted to enrich soil fertility and maintain field productivity in agricultural production systems. However, there is limited information regarding the effect of substituting mineral-N with manure on eco-efficiency (economic and environmental trade-offs) from a Life Cycle Assessment (LCA) perspective. This study investigated the eco-efficiency of maize-wheat rotation production under three fertilization strategies: mineral fertilizer NPK (CK), substituting 50% of mineral-N with solid manure (SM + NK), and substituting 50% of mineral-N with liquid manure (LM + NP) in the North China Plain. The economic profits were evaluated based on the prevailing market prices of inputs, outputs, and services. The potential environmental impacts were assessed by the LCA approach. The eco-efficiency was evaluated as the ratio of economic profit to individual environmental impact categories. The results from the economic analysis and the LCA showed that, compared with CK, the economic profit increased by 17.2% and 19.1%, while the environmental impacts at the endpoint level decreased by 24.6% and 37.9% under SM + NK and LM + NP, respectively. Additionally, the eco-efficiencies under SM + NK and LM + NP at the endpoint level were calculated to be 55.4% and 91.7%, respectively, higher than CK. Overall, the results suggested that substituting 50% of mineral-N with manure, especially liquid manure, had a great potential for sustainable maize-wheat rotation production in the North China Plain.