Compared with the lower cargo hold of the original passenger aircraft, the main cargo hold of the passenger to cargo aircraft has a larger capacity and more types of loaded cargo. Once a fire accident occurs, not only the cargo will be damaged, but also the flight safety will be affected, so it is necessary to configure the fire protection system for the main cargo hold. This paper analyzes and summarizes the composition and design points of the main cargo compartment fire protection system based on the research of aviation regulations. This paper proposes a main cargo hold smoke detection system architecture composed of smoke detectors, smoke detection system control unit, and indication alarm systems. This paper sorts out the function, performance and arrangement requirements of the equipment in the system, and provided a numerical calculation method to verify the performance of the main cargo hold smoke detection system. According to the requirements of the regulations, this paper specifies the main measures and requirements for fire suppression in the main cargo compartment, and this paper determines the arrangement requirements of portable fire extinguishers for the main cargo compartment of the passenger to cargo airplane, which is accessed by the crew during the flight.