This study aimed to investigate CCNB1, CENPF, and Neutrophils as diagnostic predictors of lung cancer and to explore their association with clinical prognosis. Clinical data were obtained for a total of 52 patients. In addition, we downloaded 555 lung cancer-related samples from the cancer genome atlas (TCGA) database. Differentially expressed genes were further screened. Immune cell infiltration and survival analysis were performed. Immunohistochemistry was used to confirm gene expression. Peripheral blood analysis showed that neutrophil percentages were significantly reduced in patients with lung cancer. The least absolute shrinkage and selection operator and multivariate regression analysis revealed that CCNB1 and CENPF were lung cancer risk factors. Both CCNB1 and CENPF are overexpressed in lung cancer. The clinical diagnostic model constructed using CCNB1, CENPF, and neutrophils had a C-index of 0.994. This model area under the curve (AUC) and internal validation C-index values were 0.994 and 0.993, respectively. The elevated expression of CCNB1 and CENPF showed that the survival rate of lung cancer patients was reduced. CCNB1 and CENPF expression was positively correlated with the clinical stage of lung cancer. Further studies confirmed that CCNB1 and CENPF are overexpressed in lung cancer tissues. The clinically constructed model with high accuracy based on CCNB1, CENPF, and neutrophils demonstrated that these are crucial indicators for lung cancer diagnosis. High expression of CCNB1 and CENPF indicates a poor prognosis in patients with lung cancer.