Objective To investigate the relationship between serum matrix metalloproteinase-9 （MMP-9）， cytokeratin 19 fragment （CYRFA21-1） and vascular endothelial growth factor （VEGF） levels and cisplatin treatment in patients with non-small cell lung cancer. Methods 130 advanced B-stage non-small cell lung cancer treated with cisplatin in Affiliated Hospital of Nantong University from December 2020 to December 2022 were selected as the study subjects； 100 patients with physical examination in our hospital were selected as the control group. By comparing the serum levels of MMP-9， CYRFA21-1 and VE GF in each group， the cisplatin treatment effect was divided into 15 patients and 37 patients in the treatment-effective group， and 78 patients in the treatment-effective group to clarify the relationship between the treatment effect of patients with non-small-cell lung cancer. Results Serum levels of MMP-9， CYRFA21-1 and VEGF were decreased in NSCLC patients after cisplatin treatment （P < 0.05）. Compared with the ineffective group， serum MMP-9， CYRFA21-1 and VEGF levels in the significantly effective group and the effective group were decreased （P < 0.05）. Logistic regression analysis showed that MMP-9， CYRFA21-1 and VEGF were also risk factors affecting cisplatin treatment effect in NSCLC patients （P < 0.05）. ROC analysis showed that serum MMP-9， CYRFA21-1 and VEGF had high predictive value for cisplatin treatment in NSCLC patients （P < 0.05）. Conclusions MMP-9， CYRFA21-1 and VEGF are highly expressed in the serum of patients with severe pneumonia， and the expression levels of MMP-9， CYRFA21-1 and VEGF are decreased after cisplatin treatment in patients with non-small cell lung cancer， which is related to the cisplatin treatment effect in patients with non-small cell lung cancer. Clinical monitoring of serum levels of MMP-9， CYRFA21-1 and VEGF can predict the therapeutic effect early to improve the prognosis of patients.