Objective Liquid biopsy technology was used to find suitable exosome-derived miRNAs as tumor biomarkers for the differential diagnosis of benign and malignant pulmonary nodules. Methods The differentially expressed miRNA markers miR-19b and miR-126 were screened by testing 24 pairs of lung cancer tissues and adjacent normal tissues. 58 patients with malignant nodules and 31 patients with benign nodules were divided in to the experimental group and the control group respectively. Plasma exosome miR-19b and miR-16 between the two groups were evaluated. With miR-16 as the internal reference, differential expression of plasma exosome miR-19b and miR-126 was statistically analyzed to explore the diagnostic value in pulmonary nodules. Results The level of miR-19b in lung cancer tissues was (45.91 ± 13.73), which was significantly higher than that in adjacent tissues (11.61±3.87) (P＜0.05). The level of miR-126 was (0.70±0.22), which was significantly lower than that of adjacent tissues (2.56±0.75) (P＜0.05). The plasma exosome of miR-19b and miR-126 in the experimental group were (1.83±0.49) and (0.83 ± 0.26) respectively, which were significantly higher than those in the control group (0.93±0.31) and (0.40±0.12) (P＜0.05). The area under the curve (AUC) of miR-19b was 0.775 in differential diagnosis between the experimental group and the control group ［AUC: 0.808 (95% CI: 0.718～0.898, P＜0.001)］, with a cutoff point of 0.936, a sensitivity of 82.8% and a specificity of 64.5%, which was higher than that of miR-126.Rank sum test was performed on the relative quantitative values of miR-19b and miR-126. In tumor size and tumor invasion group, the relative quantitative values of mir-19b were significantly different (P＜0.05). In tumor infiltration group, the relative quantitative values of mir-126 were significantly different (P＜0.05).Conclusion The relative quantification of plasma exosomal miR-19b and miR-126 can assist in the identification of benign and malignant pulmonary nodules