The use of livestock manure as a substitution for synthetic nitrogen (N) fertilizers is recommended to improve the sustainable use of manure nutrients and alleviate the adverse impacts of synthetic N fertilizers on the environment. A thorough understanding of how such substitutions affect reactive N losses and greenhouse gas (GHG) emissions in cereal production systems in the North China Plain (a main livestock production region in China), is needed to achieve an environmental friendly and sustainable production. Based on a long-term field experiment, different manure/chemical fertilizer treatments were designed, i.e., non-fertilization control (CK), chemical fertilizers alone (NPK), and manure substitution for chemical N fertilizers (with equivalent N rate; NPKP, 50% N from pig manure; NPKC, 50% N from chicken manure). Crop yield, nitrogen use efficiency (NUE), soil fertility, N losses, and GHG emissions were chosen as prominent indicators to evaluate the consequences of manure substitutions for N-based fertilizers. The replacement of synthetic fertilizers by livestock manure decreased NO3-N leaching and NH3 volatilization by 46.2% and 5.61-22.2%, respectively, while sustained the crop yields and improved NUE. However, both NPKP and NPKC treatments did not have any impact on N2O and CO2 mitigation. Compared with NPK, NPKC and NPKP meaningfully increased SOC by 9.56% and 19.6%, respectively. More specifically, NPKC increased TN content by 14.7% (P < 0.05) compared to NPK treatment. The results showed that 50% substitution of manure for synthetic N fertilizers is a potential option in maize production systems to decrease N losses (including NH3, N2O emissions and N leaching) by approximately 45% (42.8-48.1%). However, only 1.81% of the total farmers surveyed (i.e., 16,595) have being applied livestock manure for maize cultivation in the North China Plain. Therefore, famers in this plain should be encouraged to use manure to improve ecological aspects of cereal cultivation and decrease the associated environmental pollutions.