To elucidate the molecular mechanisms underlying the progression of head and neck squamous cell carcinoma (HNSCC), we investigated the function of let- 7c as a tumor suppressor. Let-7c expression was significantly down-regulated in HNSCC tumor tissues and cell lines. In vitro and in vivo studies revealed that let-7c negatively regulated HNSCC proliferation, migration and epithelial-mesenchymal transition (EMT). To explore the underlying mechanisms that affect these molecular events achieved by let-7c, we predicted its target genes. We performed luciferase assay and confirmed that insulin-like growth factor 1 receptor (IGF1R) and high mobility group AT-hook 2 (HMGA2) were the direct targets of let-7c. Knocking down of IGF1R and HMGA2 inhibited HNSCC progression, including proliferation, migration and EMT in HNSCC cells. Re-expression of these genes overcame let-7c-mediated inhibition. Taken together, our finding suggests that let-7c inhibits HNSCC progression by targeting IGF1R and HMGA2 and might be a novel target for HNSCC treatment.