The thermophoresis of suspended particles in a fluid is usually from high to low temperature. In the present paper, the negative thermophoresis (from low to high temperature) of nanoparticles in liquids is investigated by molecular dynamics simulations. It is found that the solid–liquid intermolecular coupling strength has a significant effect on the direction and magnitude of the thermophoretic force. Positive thermophoresis can be observed for strong couplings, while negative thermophoresis emerges for weak couplings. The negative thermophoresis is induced by the density gradient which pushes the particle from high to low density. Based on the analysis of the potential mean force of the solid–liquid interfacial layer, it is revealed that the switch between positive and negative thermophoresis is associated with the sign change of the averaged potential mean force for the interfacial layer. Therefore, the sign of the averaged potential mean force can be used as a criterion to predict the occurrence of negative thermophoresis. The results of this work provide insights for the microscopic manipulation of nanoparticles.