In recent years, Floquet engineering has attracted considerable attention as a promising approach for tuning topological phase transitions. In this work, we investigate the effects of high-frequency time-periodic driving in a four-dimensional (4D) topological insulator, focusing on topological phase transitions at the off-resonant quasienergy gap. The 4D topological insulator hosts gapless three-dimensional boundary states, characterized by the second Chern number $C_{2}$. We demonstrate that the second Chern number of 4D topological insulators can be modulated by tuning the amplitude of time-periodic driving. This includes transitions from a topological phase with $C_{2}=\pm3$ to another topological phase with $C_{2}=\pm1$, or to a topological phase with an even second Chern number $C_{2}=\pm2$ which is absent in the 4D static system. Finally, the approximation theory in the high-frequency limit further confirms the numerical conclusions.