Lung cancer is the most common malignancy worldwide; where non-small cell lung newlinecancer (NSCLC) constitutes ~80-85% of the total cancer as the major cancer burden. newlineLate presentation of the disease worsens the survivability of the patients due to tumor newlinetissue unavailability for biopsy; which is of paramount importance for tumor presence newlineand its information. This demands the need for improved diagnostic strategies such newlineas identifying potential circulating microRNAs (miRNAs). Notably, tumor-associated newlinecirculating microRNAs (miRNAs), stable under harsh conditions and a minimally newlineinvasive approach, might serve as a liquid biopsy to improve current diagnostic newlinestrategies for NSCLC patients. In circulation, their measured differential expression newlinecan enumerate tumor related information like early detection, tumor grade, staging, newlinehistology and metastasis. Their dysregulated profiles in human cancers are reported newlineas signature molecules for diagnosis, stage, progression, prognosis, etc. With is aim, newlinewe investigated dysregulated plasma levels of miRNAs in NSCLC samples and newlinehealthy controls through next-generation sequencing (NGS). From the NGS data, newlinecirculating miRNAs, miR-590-5p and miR-320a, showed significant down-regulation newlinewhich were further validated in eighty NSCLC and eighty healthy control plasma newlinesamples showing ~7.5-fold and ~5.8-fold significant down-regulation (Plt0.0001) newlinerespectively, through quantitative real time polymerase chain reaction (qRT-PCR). newlinev newlineNotably, patients clinico-pathological features and their overall survival status also newlineshowed negative correlation with both circulating miR-590-5p and miR-320a. newlineTo delineate the molecular mechanisms regulated by miR-590-5p and miR-320a in newlinethe progression of NSCLC, in vitro functional assays was performed in A549 cells by newlinetransfecting their inhibitor and mimics. Over-expression of these miRNAs when newlinetransfected individually in A549 cells, affected the hallmarks of cancer and resulted in newlinedecrease cell viability, proliferation, colony formation, migration and invasion newline