In this paper we study the higher-order differential variational principle and differential equations of motion for mechanical systems in event space. Based on the higher-order d'Alembert principle of the system, the higher-order velocity energy and the higher-order acceleration energy of the system in event space are defined, the higher-order d'Alembert-Lagrange principle of the system in event space is established, and the parametric forms of Euler-Lagrange, Nielsen and Appell for this principle are given. Finally, the higher-order differential equations of motion for holonomic systems in event space are obtained.