This paper provides a novel three-dimensional meshless Galerkin for horizontal well reservoir simulation. The pressure function is approached by moving least-square method which consists of weight function, basic function and coefficient.Based on Galerkin principle and use penalty function method, the paper deduces the meshless Galerkin numerical linear equations. Cut off the pressure distribution of the horizontal section from the simulation database of horizontal well reservoir. It demonstrates that meshless Galerkin is a feasible numerical method for the horizontal well reservoir simulation. It is useful to research complex reservoir.