The present field trial investigated the impacts of combined organic-inorganic fertilization (COIF) on crop quality, soil nutrients, and ecological risks (e.g., soil Cd) using the entire growth period of wheat. To do so, we set up seven different treatments in this study: control (CK); chemical nitrogen (N) fertilizer (CF); optimized fertilization (OF); organic fertilizer replacing 25% (T1) and 50% (T2) of chemical fertilizer; and organic N replacing 25% (M1) and 50% (M2) of chemical N fertilizer. Overall, our results suggested that COIF caused a significant increase in the yield of wheat. Compared with the CK, the highest wheat yield happened in M1 treatment (18.27%), although significant increases also occurred in T1 (13%), T2 (6.40%), and M2 (9.63%) treatments (P < 0.05). Besides, COIF increased the grain protein content by 31.9%. In terms of the soil properties, COIF could alleviate soil acidification while improving the cation exchange capacity (CEC). In addition, COIF treatments significantly increased the contents of total phosphorus, total potassium, available phosphorus, and available potassium, by 6.35–16.9%, 3.17–10.9%, 5.53–28.7%, and 2.6–12% (P < 0.05), respectively. Altogether, the results of the present work suggested that the replacement ratios of CF with 25%~50% cow manure are the most effective practices to improve the wheat yield, soil fertility, and the ecological sustainability of the study soils.