MicroRNA (miRNA) expression is deregulated in many types of human cancers, including thyroid cancer. The purpose of this study was to investigate miRNA deregulation in papillary thyroid carcinoma (PTC), particularly with lymph node (LN) metastasis. To identify the miRNA signature in PTC with LN metastasis, miRNAs isolated from PTC patients with LN metastasis (n = 3) and without LN (NLN) metastasis (n = 3) were used for microarray analysis. Four differentially expressed miRNAs including miR-2861, miR-451, miR-193b, and miR-1202 were selected for further validation between the LN group (n = 51) and the NLN group (n = 36) using real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The miRNA microarray results showed that compared to the NLN group, upregulation of four miRNAs including miR-2861, miR-451, miR-193b, and miR-1202 was associated with LN metastasis, whereas four other miRNAs including miR-let-7i, miR-542-5p, miR-664*, and miR-564 were downregulated in the LN group. In the validation cohort, the expression of either miR-2861 or miR-451 in the LN group was significantly greater than that in the NLN group (P = 0.004 and 0.026, respectively). Furthermore, the expression levels of miR-2861 and miR-451 in lateral lymph node (LLN) metastasis were significantly greater than those in central lymph node (CLN) metastasis (P = 0.007 and 0.001, respectively). Upregulated expression of miR-2861 and miR-451 in PTC with LN metastasis represents a unique miRNA signature associated with the prognosis and progression of PTC.