To improve vehicle side crashworthiness, this paper first introduces the negative Poisson’s ratio structure to the traditional B-pillar and proposes a negative Poisson’s ratio B-pillar. Then, the performance of the negative Poisson’s ratio B-pillar is studied in detail by comparison with a traditional B-pillar and honeycomb B-pillar. Aiming at the problem that the side crashworthiness is also significantly affected by the side structure parameters of vehicle body, the factorial analysis theory is adopted to screen out the side structure parameters with significant effect. Based on this, by combining the optimal Latin hypercube design and response surface model, a multi-objective optimization design is conducted for those structure parameters based on non-dominated sorting genetic algorithm II. Finally, the normal boundary intersection method is adopted to seek the Pareto optimal solution, and the simulation results show that compared with the traditional B-pillar, the negative Poisson’s ratio B-pillar optimized by non-dominated sorting genetic algorithm II has better comprehensive crashworthiness. The results of this paper can provide some basis for the design and optimization of vehicle side crashworthiness.