Pulmonary nodules are the main manifestations of early lung cancer. Non-small cell lung cancer is the most common histological type of lung cancer, and the main histological classification of non-small cell lung cancer is lung adenocarcinoma. The present study aimed to analyze the differentially expressed genes between patients with benign and malignant pulmonary nodules, and to identify potential therapeutic targets for lung adenocarcinoma. Sequencing data for benign and malignant pulmonary nodule samples and samples with no nodules were obtained from the National Center for Biotechnology Information Gene Expression Omnibus GSE135304 dataset. Differential gene analysis showed that S100 calcium binding protein P (S100P), ribonuclease A family member 2 (RNASE2), cytochrome c oxidase subunit 7C and mast cell expressed membrane protein 1 (C19orf59) were significantly upregulated among the blood samples collected from patients with malignant pulmonary nodules. Results from Kaplan-Meier plotter datasets showed that S100P, RNASE2 and C19orf59 were associated with the prognosis of lung cancer. RNASE2 expression was positively associated with nodule size and negatively associated with lung cancer prognosis. Moreover, RNASE2 was highly expressed in lung adenocarcinoma tissues compared with that in normal tissues. CCK-8 and Transwell assays indicated that overexpressed RNASE2 promoted the proliferation, migration and invasion of lung adenocarcinoma cells. In lung adenocarcinoma cells, RNASE2 was identified as a downstream target of microRNA (miR)-185-5p and was regulated by it. Inhibited cell proliferation, migration and invasion were observed following overexpression of miR-185-5p. Overexpression of RNASE2 reversed the inhibitory effect of miR-185-5p overexpression. In conclusion, in blood samples from patients with malignant pulmonary nodules and lung adenocarcinoma tissues, RNASE2 was found to be upregulated. High RNASE2 expression was associated with poor overall survival. miR-185-5p inhibited the proliferation, migration and invasion of lung adenocarcinoma cells by downregulating RNASE2 expression. These findings have implications for guiding therapeutic strategies.