Inclined collapse of structures under strong earthquakes threatens the adjacent infrastructures. The collapse mode and collapse direction should be considered with caution to curb the secondary disaster in the urban area. However, current studies on the inclined collapse mechanism are predominantly limited to the qualitative and intuitive understanding. To fill this gap, this study presents an insight into the inclined collapse mechanism of the reinforced concrete (RC) frame structures with two typical features subjected to earthquakes, i.e., the structures with slab opening on one side of the first floor and the structures with disparate axial compression ratios of the first story columns on the opposite sides. First, shaking table tests were performed on two 1/10-scale three-story RC frame structure models undergoing inclined collapse. Then the multi-scale finite element models were established, validated against the test results and used for parametric studies. In the parametric studies, two coefficients were considered to describe the typical features of the RC frame structures, i.e., the strong column-weak beam ratio η and differential rate of the axial compression ratios λ. The test and numerical results found that the inclined collapse mechanism was attributed to the different distributions and discrepant resistance deterioration of the plastic hinges among the first story columns of the RC frame structures with the two features. This causes the inconsistent damage levels among the first story columns, the dominant direction of the lateral displacement, and the inclined collapse of the structures. Finally, the collapse mode and collapse direction can be controlled by appropriately adjusting the two coefficients η and λ for the structures with the typical features concerned in this study.