Fine‐needle aspiration cytology and imaging examinations are commonly used diagnostic tools for papillary thyroid carcinoma (PTC). However, these methods have limitations. Inflammatory proteins have the potential to serve as diagnostic and prognostic markers, as well as treatment targets. The expression profile and diagnosis effect of inflammatory proteins in PTC are not well understood. Here, 18 healthy volunteers (as healthy control), 12 patients with nodular goiter, and 34 patients with PTC were collected to analyze serum inflammatory proteins by proximity extension assay. Receiver operating characteristic curve analysis was used to evaluate the diagnostic potential of differential expression of proteins via the area under the curve (AUC) analysis. A total of 36 differentially expressed inflammatory proteins were found among PTC, nodular goiter, and healthy control. The combination diagnosis derived from the logistic regression analysis exhibited promising diagnostic capabilities in distinguishing nodular goiter from healthy control (AUC = 0.88), distinguishing PTC from healthy control (AUC = 0.89), and distinguishing PTC from nodular goiter (AUC = 0.87). Whereas the combination diagnosis derived from the least absolute shrinkage and selection operator (LASSO) exhibited promising diagnostic capabilities in distinguishing nodular goiter from healthy control (AUC = 0.92), distinguishing PTC from healthy control (AUC = 0.93), and distinguishing PTC from nodular goiter (AUC = 0.93). Overall, this study offers potential biomarkers for distinguishing between PTC and nodular goiter in clinical practice. The combination derived from the LASSO algorithm outperforms logistic regression.