Computational human body models (HBM) present a novel approach to predict brain response in football impact scenarios, with prescribed kinematic boundary conditions for the HBM skull typically used at present. However, computational optimization of helmets requires simulation of the coupled helmet and HBM model; which is much more complex and has not been assessed in the context of brain deformation and existing simplified approaches. In the current study, two boundary conditions and the resulting brain deformations were compared using a HBM head model: (1) a prescribed skull kinematics (PK) boundary condition using measured head kinematics from experimental impacts; and (2) a novel detailed simulation of a HBM head and neck, helmet and linear impactor (HBM-S). While lateral and rear impacts exhibited similar levels of maximum principal strain (MPS) in the brain tissue using both boundary conditions, differences were noted in the frontal orientation (at 9.3 m/s, MPS was 0.39 for PK, 0.54 for HBM-S). Importantly, both PK and HBM-S boundary conditions produced a similar distribution of MPS throughout the brain for each impact orientation considered. Within the corpus callosum and thalamus, high MPS was associated with lateral impacts and lower values with frontal and rear impacts. The good correspondence of both boundary conditions is encouraging for future optimization of helmet designs. A limitation of the PK approach is the need for experimental head kinematics data, while the HBM-S can predict brain response for varying impact conditions and helmet configurations, with potential as a tool to improve helmet protection performance.