In this study, a new and efficient approach is presented for numerical solution of Fredholm integro-differential equations (FIDEs) of the second kind on unbounded domain with degenerate kernel based on operational matrices with respect to generalized Laguerre polynomials (GLPs). Properties of these polynomials and operational matrices of integration, differentiation are introduced and are ultilized to reduce the (FIDEs) to the solution of a system of linear algebraic equations with unknown generalized Laguerre coefficients. In addition, two examples are given to demonstrate the validity, efficiency and applicability of the technique.