Blockade of the RhoA-JNK-c-Jun-MMP2 cascade by atorvastatin reduces osteosarcoma cell invasion. Osteosarcoma is characterized by a high malignant and metastatic potential, which points to the need for new therapeutic strategies to prevent cell metastasis. In this study, we show that statin-induced HMG-CoA reductase inhibition reduces cell migration and invasion in human and murine osteosarcoma cells, independently of the genotype. The statin-induced reduction of cell migration and invasion was independent of induction of apoptosis and was geranylgeranylpyrophosphate-dependent. The statin reduced matrix metalloproteinase (MMP) 2, 9, and 14 and TIMP2 expression or activity in invading cells. Forced expression of MMP2 and MMP14 overcame the inhibitory effect of the statin on cell invasion, suggesting a role for these MMPs in invasive potential. We also investigated the mechanisms involved in the reduced MMP2 activity and cell invasion. Inhibition of JNK, but not ERK1/2 signaling, reduced MMP2 activity. Pharmacological or constitutive activation of JNK overcame the reduced MMP2 activity and cell invasion induced by the statin. The statin decreased JNK phosphorylation and c-Jun nuclear translocation, suggesting that HMG-CoA reductase inhibition targets the JNK-c-Jun signaling pathway. We showed that mevalonate or geranylgeranylpyrophosphate treatment prevented the statin-induced reduction in JNK phosphorylation, MMP2 activity, and cell invasion. Forced expression of a constitutively active form of RhoA increased JNK phosphorylation and overcame the inhibitory effect of atorvastatin on MMP2 activity and cell invasion. The data establish a link between RhoA, JNK, c-Jun, and MMP2 activity that is functionally involved in the reduction in osteosarcoma cell invasion by the statin. This suggests a novel strategy targeting RhoA-JNK-c-Jun signaling to reduce osteosarcoma cell tumorigenesis.