The present study aimed to figure out the potential role of exosomal microRNAs, and their targeted genes in HNC detection/diagnosis. In the present study, exosomes were extracted from the serum samples of 400 HNC patients and 400 healthy controls. Exosomes were characterized using TEM, NTA, TEM-immunogold labeling and ELISA. Quantitative PCR was used to measure the expression level of exosomal miRNA-19a, miRNA-19b and targeted genes and in HNC patients and controls. The deregulation of miR-19a (p < 0.01), miR-19b (p < 0.03), (p < 0.04) and (p < 0.04) was observed in HNC patients vs controls. ROC curve and Kaplan-Meier analysis showed the good diagnostic/prognostic value of selected exosomal microRNAs and related genes in HNC patients.