SignificanceSeveral developmental and physiological processes require that cells display a controlled ability to migrate in an orientated manner. This capacity is also reacquired by certain cancer cells during their progression toward aggressiveness that allows them to establish distant metastases. The Rho GTPases are instrumental in the control of orientated migration. Here, we demonstrate that the estrogen-related receptor α (ERRα), whose high expression correlates with tumor aggressiveness and poor prognosis, decreases the stability and activity of the RHOA protein and induces orientated cell migration. Together with other published data, our results show that inactivation of ERRα may reduce tumor aggressiveness.