This paper discusses integrated safety monitoring system design of in-flight aircraft. During a flight mission, the aircraft, the operation of crew members and the dynamic change of flight environments interacts as a system. The change of safety situation of an aircraft should be attributed to the behavior of those human-machine-environment factors, which established the basis of the in-flight safety monitor system designing. The research extends the implementation of Prognostic and Health Management (PHM) methodology from aircraft system health to aircraft in-flight safety. An integrated safety monitoring function architecture that developed on the platform of Centralized Maintenance System (CMS) is presented. Starting with identification and selection of a set of flight safety situation indicators that describe the risk level of aircraft system, the safety monitoring system should detect and monitor the operation of crew members, the condition of systems and components and advert of flight environments in a real-time or near real-time manner, determine and assess the safety level of the aircraft instantly, detect and track errors of human operation, anomalies of systems, and abnormal event of flight environment, diagnose the causes for the above abnormal events, and estimate the near future safety situation of the current flight aircraft. During a flight, if there are any abnormal event that may led to a critical safety situation is being detected, the flight safety monitoring system should also trigger a alert or warning report, present the relationship between the information of a abnormal event and its root cause, its effects and consequences, and the emergency response knowledge for it, provide crew members with situational awareness of the system safety, and promote better safety decision support. The technologies and tools for the implementation of flight safety monitoring and early warning are also discussed.