Objectives This study aims to assess the capability of monocyte-to-lymphocyte ratio (MLR) and C-reactive protein (CRP) to diagnose and differentiate diagnosis various types of lung diseases, including non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC) and benign pulmonary diseases (BPD). Methods Patients diagnosed with lung cancer and BPD by pathology and healthy volunteers were enrolled. Laboratory test data and clinical pathologic characteristics were recorded, including complete blood counts, CRP, NSE, CYFRA21-1 levels, age, gender, and histological type. The differences between the groups were calculated and compared. Receiver operating characteristic (ROC) analysis was performed to specify the diagnostic value of MLR and CRP in NSCLC, SCLC, and BPD. Results A total of 2042 patients and 996 healthy volunteers were involved (NSCLC, SCLC, and BPD patients were 1,245, 302, and 495, respectively). Compared to healthy volunteers, MLR and CRP in patients with NSCLC, SCLC, and BPD were significantly higher (p<0.0001). The areas under the curve (AUC) were 0.703, 0.828, 0.784, 0.703, 0.813, and 0.798, respectively. Through the combined analysis of MLR and CRP, the AUC could be improved to 0.765, 0.882, and 0.843, respectively. Additionally, an evaluation of the diagnostic value of MLR+CRP+ NSE+CYFRA21-1 gave the AUC of 0.898 (95 % CI:0.882–0.914), 0.986 (95 % CI:0.975–0.996) and 0.925 (95 % CI:0.906–0.945), respectively. Moreover, MLR and CRP could differentiate early-stage patients (0 and I stages) from late-stage (IV stage) for NSCLC and SCLC patients, with p-values of less than 0.0001, respectively. Conclusions MLR and CRP could be good diagnostic indicators of lung diseases, especially for SCLC and BPD. Both could improve the diagnostic efficiency of traditional lung cancer biomarkers, demonstrating excellent diagnostic value, particularly in SCLC. This may supply early treatment and survival advantages for patients.