This study aimed to investigate the regulatory role and mechanism of microRNA-766 (miR-766) on cutaneous squamous cell carcinoma (CSCC) cells. Methods: The expression of miR-766 and programmed cell death 5 (PDCD5) was detected in CSCC tissues and CSCC cell lines (A431, SCL-1 and DJM-1 cells) by qRT-RCR. The proliferation, colony-forming ability, apoptosis, migration and invasion of A431 and SCL-1 cells was measured by MTT, colony formation, flow cytometry, wound healing and transwell assay, respectively. The interaction between miR-766 and PDCD5 was detected by dualluciferase reporter gene assay. The expression of matrix metalloproteinase 2 (MMP-2), MMP-9 and PDCD5 was measured by Western blot. In addition, A431 cells were subcutaneously injected into mice, and the tumor volume and weight were measured. Results: MiR-766 was upregulated, and PDCD5 was downregulated in CSCC tissues and cells. MiR-766 significantly promoted the proliferation, migration and invasion, and inhibited the apoptosis of A431 and SCL-1 cells. MiR-766 also significantly increased the expression of MMP-2 and MMP-9 in A431 and SCL-1 cells. PDCD5 was a target gene of miR-766. PDCD5 significantly reversed the tumor-promoting effect of miR-766 on A431 and SCL-1 cells. In addition, miR-766 inhibitor inhibited the tumor growth in mice. Conclusion: MiR-766 inhibitor inhibited the proliferation, migration and invasion, and promoted the apoptosis of CSCC cells via downregulating PDCD5.