Thin-walled tubes have been predominantly utilized in passive vehicle safety systems as crash energy absorbers. With the increasing popularity of additive manufacturing technique, it is feasible to fabricate novel internal reinforcement structures to further reinforce the crashworthy performances of thin-walled tubes. In the present work, a novel nonuniform Lattice-reinforced multi-cell tube based on topology optimization was put forward to explore the crashworthy performances under axial loading and lateral bending. Numeric models validated against the experiments were established to reveal the crashworthy performances of lattice material infilled multi-cell tubes (MCTs). It is observed that the optimized nonuniform lattice structure absorbs more energy than the uniform counterpart. In addition, the hybrid multi-cell filled tubes exhibit remarkable improvements in terms of energy absorption and crushing force efficiency in contrast to the corresponding empty tubes. Furthermore, the specific energy absorption of the three-layer hybrid multi-cell tube is improved by 38.2% and 20.0% under two loading conditions respectively relative to the sum of individual components on account of interplay effect. Collectively, the hybrid nonuniform lattice reinforcement tube provides a promising method for the crashworthy design of MCTs, which can be recommended as an underlying candidate for passive safety protection applications.