miRNA-22 (miR-22) has been showed to involve in a variety of cancers; however, the association between miR-22 expression level and the prognosis of osteosarcoma is also poorly unknown. Fifty-two patients with surgically resected paired osteosarcoma and non-neoplastic disease between 2008 and 2014 were involved in this study. Real-time PCR was performed to examine the expression level of miR-22 in osteosarcoma tissues and noncancerous bone tissues. Then the association between miR-22 expression and clinical–pathological parameters were further evaluated. Kaplan–Meier analysis and Cox proportional hazards regression models were explored to reveal the correlations of miR-22 expression with survival of patients. The results indicated that miR-22 was downregulated in osteosarcoma tissues in comparison with noncancerous bone tissues. In addition, there is statistically significance between miR-22 expression level and recurrence, metastasis, and chemotherapy response. The patients with lower miR-22 expression level had both poorer overall survival and disease-free survival. The multivariant analysis revealed that the miR-22 expression level and metastasis status are independent prognosis factors for osteosarcoma. In conclusion, miR-22 was downregulated in osteosarcoma and its expression level was correlated with a variety of important clinical–pathological parameters. Moreover, miR-22 may serve as a promising biomarker for predicting the prognosis of osteosarcoma.