An operation control system and method of a fuel cell vehicle are provided. The system includes a fuel cell, an air supply device operated by a motor, to supply air to the fuel cell and a sensing unit that senses an abnormal operation of the air supply device. A calculation unit calculates a lower-limit voltage of the air supply device required for normal operation of the air supply device when the sensing unit senses abnormal operation of the air supply device. A controller then adjusts a voltage supplied to the air supply device based on the calculated lower-limit voltage.