Objective To investigate the changes of serum insulin-like growth factor-1 (IGF-1), cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) and pro-gastrin-releasing peptide (ProGRP) levels in patients with papillary thyroid microcarcinoma (PTMC). Methods A total of 60 patients with PTMC who were treated in Xuchang People's Hospital from March 2024 to November 2024 were collected as the study group. In addition, 60 patients with micronodular goiter were collected as the control group. Compare the serum levels of ProGRP, IGF-1 and CYFRA21-1 between the two groups, further analyze the above indexes in patients with different clinical stages (stage Ⅰ-Ⅱ, stage Ⅲ-Ⅳ) and different prognoses, and adopt receiver operating characteristic (ROC) curve to analyze the combined predictive value. Results The serum levels of ProGRP and CYFRA21-1 on admission in the study group and stage Ⅲ-Ⅳ patients were higher than those in the control group and stage Ⅰ-Ⅱ patients, while IGF-1 levels were lower (P<0.05); the levels of ProGRP and CYFRA21-1 were positively correlated with clinical stage, and IGF-1 was negatively correlated with it (P<0.05). At 1 and 3 months after treatment, patients with good prognosis presented lower serum ProGRP and CYFRA21-1 levels and higher IGF-1 levels compared with those with poor prognosis (P<0.05). The AUC of ProGRP, IGF-1 and CYFRA21-1 levels combined to predict poor prognosis at 1 month and 3 months of treatment were 0.858 and 0.901, respectively. Conclusion The abnormal expression of serum ProGRP, IGF-1 and CYFRA21-1 in PTMC patients can predict the risk of poor prognosis of PTMC, which is of positive significance for improving the clinical prognosis of patients.