Objective To investigate the impact and mechanisms of periostin (POSTN), Krebs von den Lungen-6 (KL-6), pulmonary surfactant protein A (SP-A), and pulmonary surfactant protein D (SP-D) on the diagnosis and disease assessment of idiopathic pulmonary fibrosis (IPF), and conduct a comparative analysis. Methods From October 2022 to October 2023, a total of 55 patients diagnosed with IPF and treated at the Third Affiliated Hospital of Anhui Medical University were enrolled as an IPF group. Additionally, 30 patients with bacterial pneumonia and 30 healthy individuals undergoing concurrent health examinations during the same period were selected as a pneumonia control group and a healthy control group, respectively. All participants underwent enzyme-linked immunosorbent assay to measure serum levels of POSTN, KL-6, SP-A, and SP-D, along with pulmonary function tests. The IPF patients also underwent high-resolution computed tomography (HRCT) and echocardiography to quantify HRCT scores and pulmonary artery systolic pressure (PASP). Receiver operating characteristic (ROC) curves were plotted to analyze the significance of serum POSTN, KL-6, SP-A, and SP-D levels in IPF diagnosis. Pearson and Spearman correlation tests were used to analyze the relationships between these biomarkers and pulmonary function, PASP, and HRCT scores. Results Serum concentrations of POSTN, KL-6, SP-A, and SP-D were significantly elevated in the IPF group compared with the pneumonia group and the healthy controls (P<0.05), while serum levels of SP-A and SP-D were notably higher in the pneumonia group compared with the healthy control group (P<0.05). Within the IPF group, serum POSTN levels were negatively correlated with forced expiratory volume in the first second as a percentage of predicted value (FEV1%pred) and diffusion capacity of the lung for carbon monoxide as a percentage of predicted value (DLCO%pred) (P<0.05); KL-6 and SP-D levels were also negatively correlated with FEV1%pred, forced vital capacity as a percentage of predicted value (FVC%pred), and DLCO%pred (P<0.05); and the concentration of SP-A was negatively correlated with DLCO%pred and positively correlated with PASP (P<0.05). Additionally, serum levels of POSTN, KL-6, and SP-A in the IPF group showed significant positive associations with HRCT scores (P<0.01). Conclusions POSTN is a valuable serum biomarker for IPF, exhibiting the highest sensitivity and specificity among the four serum markers, with diagnostic performance superior to KL-6, SP-A, and SP-D. POSTN, KL-6, SP-A, and SP-D can all be used for the diagnosis and assessment of IPF.