One of the most recent of tumor molecular characterization approaches is the microRNA (miR) expression profile. No single marker is sufficiently accurate for clinical use. Numerous biomarkers panels were created for three main purposes: tumor subtype, classification and, early detection, and prediction of tumor responses to treatment and prognosis of patients. miR-21-5p and miR-126-3p have received special attention because of their relationship with many cancer sites such as lung cancer, colorectal cancer, and renal cell carcinoma. We aimed to study their diagnostic and prognostic utility in lung cancer patients. Serum carcinoembryonic antigen (CEA) level was measured using an enzyme-linked immunosorbent assay (ELISA) technique. The expression levels of miR-21-5p and miR-126-3p were determined by real-time PCR in 60 non small cell lung cancer (NSCLC) patients and 40 healthy controls to detect diagnostic utility. Moreover, it was correlated with all disease clinicopathological characters and patient survival. Higher miR-21-5p and lower miR-126-3p levels were found in lung cancer patients than in controls. The sensitivity of CEA and miR-21-5p and miR-126-3p were 78.3, 96.7, and 90% at cutoff points 7.5, 2.35, and 2.175, respectively to distinguish NSCLC patients from controls. On combining both miR-21-5p and miR-126-3p, an improvement of sensitivity to 97% was noted. For patients, miR-21-5P increased significantly with metastatic stage and the highest grade (GIII). There was significantly longer overall survival (OS) among patients with early stages, lower grades GI&II, low miR-21-5p, and high miR-126-3p. miR-126-3p and presence of metastasis, the last two factors were the independent factors affecting OS with a hazard ratio of 0.26 (95% CI: 0.06-1.09) and 3.64 (95% CI: 1.22-16.5), respectively. Circulating miR-21-5p and miR-126-3p may play a significant role in diagnosis and prognosis in NSCLC patients.