Objective To investigate the prognostic value of C-C motif chemokine ligand 11 (CCL11) and midkine (MK) in serum of patients with differentiated thyroid carcinoma (DTC). Methods One hundred and fifty patients with DTC admitted in Henan Provincial People's Hospital from January 2015 to January 2017 were selected as DTC group, 150 patients with benign thyroid disease in the same period were selected as benign group, and 150 healthy volunteers were selected as control group. The serum CCL11 and MK levels of the three groups were compared. Patients in DTC group were divided into survival subgroup and death subgroup according to their prognosis. The clinical data between survival and death patients were compared. Cox regression analysis was used to analyze the factors affecting the prognosis of DTC patients. The receiver operating characteristic (ROC) curve was established to evaluate the diagnostic value of serum CCL11 and MK levels in the prognosis of DTC. Results Compared with control group, the levels of serum CCL11 and MK increased in DTC group and benign group, and the levels were higher in DTC group than in benign group (P<0.05). On the 3rd day after operation, the levels of serum CCL11 and MK were lower in both DTC group and benign group than those at the time of diagnosis, and still higher in DTC group than in benign group (P<0.05). In DTC group, 135 patients survived and 15 died. The age, tumor diameter, TNM stage, lymph node metastasis, capsular invasion, differentiation degree and serum thyroglobulin (Tg), CCL11, MK levels were significantly different (P<0.05) between the survived and dead patients with DTC. Cox regression analysis showed that TNM stage, lymph node metastasis and serum Tg, CCL11, MK levels were the prognostic factors of DTC (P<0.05). The results of ROC analysis showed that serum CCL11 and MK levels were of high value in diagnosis of DTC prognosis, and the diagnostic efficiency was higher when they were combine used (sensitivity 93.33%, specificity 73.33%, AUC 0.835). Conclusions The serum levels of CCL11 and MK were abnormally elevated in patients with DTC. The combined detection of serum levels of CCL11 and MK might have higher prognostic diagnostic value for DTC.