A cylinder de-activation control method and a cylinder de-activation system are disclosed. A cylinder de-activation control method of an engine having an odd number of cylinders may include: receiving operation state signals of a vehicle; determining whether the operation state signals correspond to a CDA mode driving region of a CDA apparatus; preparing a CDA driving mode of the CDA apparatus when the operation state signals correspond to the CDA mode driving region; and performing a CDA mode conversion on each cylinder.