Objective To investigate the expression levels of serum Chemokine C-X-C motif ligand 14 (CXCL14), connective tissue growth factor (CTGF) and interleukin-6 (IL-6) inpatients with different prognosis, and to analyze the correlation between the three and the severity of the disease and the predictive value of combined detection for the prognosis of patients with idiopathic pulmonary fibrosis (IPF). Methods A total of 103 patients with IPF admitted to Puyang Anyang Prefecture Hospital hospital from June 2022 to April 2023 were selected as the research objects. The patients were divided into good prognosis group (46 cases) and poor prognosis group (57 cases) according to the prognosis after 6 months of treatment. The serum levels of CXCL14, CTGF, and IL-6 between the two groups before treatment and one month after treatment were compared, as well as the pulmonary function parameters [total lung capacity (TLC), vital capacity (VC), and the ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC)] and high-resolution CT (HRCT) scores one month after treatment. The correlations of serum CXCL14, CTGF, and IL-6 levels with both the pulmonary function parameters and HRCT scores were analyzed, and the predictive value of combined detection of these serum markers for the prognosis of IPF was evaluated. Results After one month of treatment, the levels of serum CXCL14, CTGF, IL-6 and the HRCT score in the poor prognosis group were higher than those in the good prognosis group, and the lung function indexes were lower than those in the good prognosis group, the differences were statistically significant (P<0.05); after one month of treatment, the levels of serumCXCL14, CTGF and IL-6 and the HRCT score were lower than those before treatment, and the lung function index was higher than that before treatment, the differences were statistically significant (P<0.05); the levels of serumCXCL14, CTGF and IL-6 was negatively correlated with lung function index and positively correlated with HRCT score, and the differences were statistically significant (P<0.05); the AUC of the levels of serum CXCL14, CTGF and IL-6 and combined prediction of poor prognosis in IPF patients were 0.788, 0.757, 0.819, 0.912, and the value of combined detection was higher than that of single index detection, the differences were statistically significant (P<0.05). Conclusion The levels of serum CXCL14, CTGF and IL-6 is closely related to the prognosis of IPF, and the combined detection of the three can provide an effective reference for predicting the poor prognosis of IPF patients.