Circulating microRNAs (miRNAs) have been demonstrated as robust and promising biomarkers for non-small cell lung cancer (NSCLC). Our aim was to determine the significance of serum exosomal miR-382 in NSCLC. Circulating exosomes were collected from 126 patients with NSCLC and 60 normal controls before treatment and one month after surgery. The circulating exosomal miR-382 expression was measured with quantitative RT-PCR (qRT-PCR) in all the participants. Our findings demonstrated that circulating exosomal miR-382 was very reduced in NSCLC. In addition, it showed high accuracy for discriminating NSCLC patients from healthy subjects. Interestingly, serum exosomal miR-382 improved the diagnostic accuracy of carcinoembryonic antigen (CEA). Moreover, its level increased significantly one month following surgical resection. Reduced circulating exosomal miR-382 was positively associated with poor clinical variables. NSCLC cases with lower serum exosomal miR-382 suffered worse overall survival (OS) and serum exosomal miR-382 was independently associated with OS. Taken together, circulating exosomal miR-382 is a robust biomarker for evaluating the progression of NSCLC. IJCEP Copyright © 2021.