Background: Interleukin-22 (IL-22) is one of the cytokines secreted by T-helper 17 (Th17) cells. It belongs to the IL-10 cytokine family and influences a variety of immune reactions. Studies have indicated that IL-22 can promote cancer progression and metastases. However, the function of IL-22 in osteosarcoma (OS) remains unclear. Material/Methods: In this study, the expression of IL-22 in the OS cell line was detected by qRT-PCR. The role of IL-22 in proliferation and invasion in OS cells was tested by MTT and Transwell assays. The protein expression of STAT3, phospho-STAT3, AKT, and phospho-AKT was detected by Western blot analysis. Results: The results showed that IL-22 was upregulated in OS cells. IL-22 dose-independently promoted OS cells proliferation and invasion, which could be reversed by IL-22 antibody or STAT3 siRNA. Furthermore, IL-22 exposure of OS cells resulted in dose-independently increased levels of phosphorylated STAT3 protein kinases. Interestingly, IL-22 did not influence the expression of phosphorylated AKT. Conclusions: These results suggest that IL-22 promotes OS cells proliferation and invasion and its effect is mediated by activation of the STAT3 pathway. These findings demonstrate that IL-22 may serve as a promising molecular biomarker for diagnosis and therapy for OS patients.