Objective To explore the clinical value of red blood cell volume distribution width coefficient of variation (RDW-CV), serum interleukin-11 (IL-11) and interleukin-31 (IL-31) in the diagnosis of interstitial lung disease (ILD). Methods Prospectively selected 46 ILD patients admitted to the Department of Respiratory and Critical Care Medicine, the Affiliated Hospital of Chengde Medical University from November 2022 to October 2023 were set as ILD group, 40 patients with community-acquired pneumonia (CAP) as CAP group, and 35 healthy examiners as control group. The ILD group was further divided into idiopathic interstitial pneumonia (IIP) subgroup (n=30) and connective tissue disease-related ILD (CTD-ILD) subgroup (n=16) based on clinical diagnosis. General and clinical data of each group were recorded, and RDW-CV and serum IL-11 and IL-31 levels were detected in each group. The ILD group was tested for alveolar arterial oxygen pressure difference (AaDO₂) and arterial blood oxygen pressure (PaO₂), and calculated the oxygenation index (OI). The correlation between the levels of RDW-CV, IL-11 and IL-31 and the severity of ILD were analyzed to explore the value of the above indicators in the clinical diagnosis of ILD and the differential diagnosis of different types of ILD. Results Compared with control group, there was no statistically significant difference in general information such as age, gender, smoking history, and complications between the ILD and CAP groups (P<0.05); RDW-CV, absolute values of neutrophil count (NEUT), and serum IL-11 and IL-31 levels in ILD group were significantly increased (P>0.05). Compared with CAP group, the levels of RDW-CV and serum IL-11, IL-31 in ILD group were increased, while the level of serum C-reactive protein (CRP) was decreased, with statistically significant differences (P<0.05). Correlation analysis results showed that RDW-CV and serum IL-31 in ILD patients were negatively correlated with OI (P<0.05), and positively correlated with AaDO₂ (P<0.05). The area under the ROC curves (AUC) of RDW-CV and serum IL-11, IL-31 single and combined applications for diagnosing ILD were 0.770, 0.666, 0.646, and 0.854, respectively (P<0.05). The AUC of serum IL-11 for differential diagnosis of CTD-ILD and IIP was 0.727(95%CI 0.580-0.874), with sensitivity of 62.5% and specificity of 73.3% (P<0.05). Conclusions RDW-CV and serum IL-31 have certain value in assessing the severity of ILD. RDW-CV and serum IL-11 and IL-31 have certain value in the diagnosis of ILD. Serum IL-11 has certain value in the differential diagnosis between CTD-ILD and IIP.