This dissertation presents an investigation and design optimization of energy absorbent protective systems that protect the brain. Specifically, the energy absorption characteristics of the bighorn sheep skull-horn system were quantified and used to inform a topology optimization performed on a football helmet facemask leading to reduced values of brain injury indicators. The horn keratin of a bighorn sheep was experimentally characterized in different stress states, strain rates, and moisture contents. Horn keratin demonstrated a clear strain rate dependence in both tension and compression. As the strain rate increased, the flow stress increased. Also, increased moisture content decreased the strength and increased ductility. The hydrated horn keratin energy absorption increased at high strain rates when compared to quasi-static data. The keratin experimental data was then used to inform constitutive models employed in the simulation of bighorn sheep head impacts at 5.5 m/s. Accelerations values as high as 607 G’s were observed in finite element simulations for rams butting their heads, which is an order of magnitude higher than predicted brain injury threshold values. In the most extreme case, maximum tensile pressure and maximum shear strains in the ram brain were 245 kPa and 0.28, respectively. These values could serve as true injury metrics for human head impacts. Finally, a helmeted human head Finite Element (FE) model is created, validated, and used to recreate impacts from a linear impactor. The results from these simulations are used to train a surrogate model, which is in turn utilized in multi-objective design optimization. Brain injury indicators were significantly reduced by performing multi-objective design optimization on a football helmet facemask. In particular, the tensile pressure and maximum shear strain in the brain decreased 7.5 % and 39.5 %, respectively when comparing the optimal designs to the baseline design. While the maximum tensile pressure and maximum shear strain values in the brain for helmeted head impacts (30.2 kPa and 0.011) were far less than the ram impacts (245 kPa and 0.28), helmet impacts up to 12.3 m/s have been recorded, and could easily surpass these thresholds.