Background: The diagnostic value of periostin and Krebs von den Lungen-6 (KL-6) in idiopathic pulmonary fibrosis (IPF) has been reported, but the superiority of serum periostin or KL-6 as a biomarker in early-onset IPF is yet to be determined. Methods: A total of 51 IPF patients with anti-fibrotic therapy who underwent twice high-resolution computed tomography (HRCT) fibrosis scoring evaluation and 27 healthy controls were retrospectively enrolled from the First Affiliated Hospital of Guangzhou Medical University between January 2020 and May 2022. Serum levels of periostin and KL-6 by enzyme-linked immunosorbent assay (ELISA) and clinical diagnosis test were evaluated in both cohorts. Results: The levels of serum KL-6 levels in patients with initial diagnosis and with anti-fibrotic therapy decreased from 1680.71 ± 1842.60U/mL to 1263.25 ± 1488.19 U/mL (P<0.05), while serum periostin levels decreased from 73.92 ± 13.48pg/mL to 43.78 ± 15.52 pg/mL (P<0.001). In survival probability analysis, the combined performance of periostin-KL-6 was noteworthy compared with periostin and KL-6 alone (AUC: 0.894, 0.875, 0.639, respectively). Significant performances were observed between periostin levels and total fibrosis score < 100 than KL-6 in the stage of early-onset IPF (r: 0.2266 > 0.1118), while KL-6 showed a better when total fibrosis score > 100, namely in the later stage of IPF (r: 0.2197 > 0.1050). Conclusions: Our findings indicate that serum periostin expression was more remarkable than KL-6 in the early-onset IPF diagnosis (Total fibrosis score < 100), and innovative HRCT fibrosis score stratification was a significant extention in IPF patients.