Objective To explore the correlations of plasma D-dimer and fibrinogen levels with carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA21-1) in patients with non-small cell lung cancer (NSCLC). Methods The clinical data of 196 patients with NSCLC diagnosed for the first time in the Department of Respiratory and Critical Care Medicine, the 416 Hospital of Nuclear Indusry between July 2017 and December 2019 were analyzed retrospectively. There were 57 cases in early stage (stage Ⅰ-Ⅱ), 57 cases in medium stage (stage Ⅲ), and 82 cases in advanced stage (stage Ⅳ) according to TNM staging, 108 cases of adenocarcinoma, 87 cases of squamous cell carcinoma, and 1 case of unclassified type according to pathological classification, and 19 deaths and 177 survivals according to outcome. The levels of D-dimer and fibrinogen were determined by immunoturbidimetry and coagulation method, and the levels of CEA and CFYRA21-1 were determined by electro-chemiluminescence method. The non-normally distributed data were presented as median (lower quartile, upper quartile), and Spearman correlation analyses were performed. Results Among the early, middle and advanced stage patients, the levels of D-dimer [198.00 (133.00, 390.87), 279.00 (170.93, 520.89), 389.00 (196.25, 931.00) μg/L], CEA [3.20 (2.60, 5.17), 13.53 (5.07, 70.63), 15.69 (4.07, 123.46) μg/L], and CFYRA21-1 [4.79 (3.15, 8.84), 8.60 (4.83, 19.32), 7.19 (3.09, 15.05) μg/L] were significantly different (P<0.05); however, there was no statistical difference in the level of fibrinogen among the three stages (P>0.05). The level of CYFRA21-1 in the adenocarcinoma group was lower than that in the squamous cell carcinoma group [(5.39 (2.81, 12.71) vs. 6.86 (4.18, 12.29) μg/L, P<0.05], while there was no statistically significant difference in D-dimer, CEA, or fibrinogen between the two groups (P>0.05). The levels of D-dimer, CEA, and CFYRA21-1 in the death group [1176.00 (382.00, 2848.00), 135.34 (24.85, 403.50), 10.82 (7.41, 23.41) μg/L] were significantly higher than those in the survival group [270.00 (146.00, 481.50), 5.62 (3.05, 26.53), 6.28 (3.37, 12.30) μg/L], and the differences were statistically significant (P<0.01); but there was no statistical difference in the level of fibrinogen between the two groups (P>0.05). D-dimer was positively correlated with CEA and CFYRA21-1 (rs=0.450, 0.291; P<0.001), but fibrinogen was not correlated with CEA or CFYRA21-1 (P>0.05). Conclusion D-dimer was more valuable than fibrinogen in predicting the clinical stage and prognosis of NSCLC.