A non-uniform displacement engine control system employing cylinder deactivation includes a non-uniform displacement engine including a plurality of cylinders, the cylinders including at least two sizes of cylinders having different displacements, a motor connected to a driving shaft of the engine, a battery for supplying electrical energy to the motor, and a motor control unit for controlling the motor, wherein the motor control unit controls total torque by adjusting motor driving torque or energy regeneration torque and performs control such that cylinder deactivation (CDA) is performed after selectively performing a transient state transition based on a previous control mode at a time of switching to a CDA control mode.