Spray combustion in compression ignition (CI) engines is a complex physical-chemical phenomenon. The differences in key fuel properties between gasoline range fuels and diesel, including the distillation temperature ranges and fuel reactivity, affect spray formation and combustion. To understand the impact of these fuel effects, this study aims at a thorough computational investigation involving variations in both the fuel physical and chemical properties. Physical properties include latent heat of vaporization, specific heat capacity, density, vapor pressure, viscosity, and surface tension. These properties were individually perturbed between gasoline and diesel. Chemical properties were represented by different fuel reactivity, including PRF0 and PRF60. The model was validated against diesel and RON60 gasoline spray experiments performed in a constant-volume combustion chamber. The physical and chemical properties were modeled separately to isolate the effect of a single parameter that is often difficult to single out in experimental investigations. Sprays under non-reacting and reacting conditions were then simulated to understand the physical processes that lead to ignition and thus the fuel reactivity effects on the subsequent processes. The investigation covered low to high temperature combustion and different exhaust gas recirculation (EGR) levels. Simulation results suggested that the chemical property dominated the ignition process, whereas the physical properties had more influence on the atomization and vaporization process. Also, there was a complex interaction between physical and chemical parameters on spray ignition depending on the operating conditions, which provide insights on tailoring fuel properties for different CI applications.