Liver injury is one of the most fatal injuries in traffic accidents. To deeply study response characters of this injury under the unique impact condition, three impact tests are conducted based on the human body model and constraint systems of a car. This study is conducted based on the numerical method and adopts the orthogonal experimental design to deeply investigate the relationship between biomechanical responses and the impact loading variables. Data were collected and analyzed with the rotation of the liver in three planes and the distance change relative to the spine. Results show that in the near-side oblique impact, the maximum stress of the liver is captured as 10.041 MPa. In addition, the rotation angle of the liver in the three planes is the largest in the far-side oblique collision. In general, a more significant influence on the compression and movement of the liver is obtained from the near-side side collision, mainly because the door directly hits the left side of the occupant during crash process due to the limited space between door and occupant. In a far-side oblique collision, a buffering effect of the seat back to the driver does not play the role during the crash. As a result, the seatbelt slips off the occupant’s shoulder, resulting in a high displacement of the upper body. Thus, ensuring the restraint effect of the seatbelt may be a crucial problem for far-side oblique collision. This study can provide a reference to the occupant safety protection during vehicle accidents.