Motorcycle frontal crashes usually cause serious and fatal head injuries to riders. This paper presents a two-level factorial experiment through finite element simulations of motorcycle-rigid wall impact scenario to investigate the effects of motorcycle layout design variations on rider's relative head injury risks, and also of the deformation mechanisms of motorcycle frontal structures on dynamics of the motorcycle. The motorcycle layout design variations were represented by the changes of three design factors, namely location of the engine block, location of air filter casing and its orientation. Head Injury Criteria (HIC15) based on a time interval of 15 ms were selected as the response variable to evaluate the effects of the corresponding changes. The analysis showed that HIC15 values were significantly influenced by the changes of these factors, with the differences ranging from -21% to +11% for seven different designs of motorcycle layout as compared to the original one. Such influences on HIC15 values were mainly due to the changes in motorcycle dynamics caused by different deformation mechanisms of the wheel, which was attributed to interactions between the frontal structures and the engine block and also air filter casing. It was also found that HIC15 values were significantly influenced by the vertical component of motorcycle accelerations, but not by the horizontal component. A regression model for predicting the HIC15 value was established and the effect plots of the factors were also produced from the factorial analysis and it was found that there were interactions between the effect of the design factors. The outcomes of the present study provide an insight into how the structural response of the frontal structures of motorcycles could be taken into consideration as part of design elements in reducing rider's head injury risks in frontal crashes.