The invention discloses a multi-layer large-span fabricated orthogonal-diagonal lattice concrete space grid box-type structure and a manufacturing method. The planes of concrete floors of a multi-layer large-span building are narrow and long, and the ratio Lx/Ly of the long edges to the short edges is larger than 1.5. A peripheral supporting structure system of the prefabricated large-span orthogonal-diagonal lattice concrete hollow floors is changed into a concrete grid type framework with dense columns and dense beams from a concrete framework structure formed by casting of large column grids in site, and it is required that the sizes of floor grids are equal to the sizes of dense column grids. Small connecting beams are arranged at an upper window opening and a lower window opening of each layer of dense columns except connecting beams at the floor, so that the peripheral supporting structure system is changed into the grid type framework from the framework. Because the transverse floors and the vertical supporting system both are composed of grids, the structure system is changed into the novel orthogonal-diagonal lattice space grid box-type structure system of a mechanical model with plates.