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Safety is of paramount concern in aerospace and aviation. Safety has evolved over the years, from the technical era to the human-factors era and organizational era, and finally to the present era of systems-thinking. Building upon three foundational concepts of systems-thinking, a new safety concept called “integration-in-totality principle” is propounded in this article as part of a “seven-principles-framework of system safety”, to act as an integrated framework to visualize and model system safety. The integration-in-totality principle concept addresses the need to have a holistic ‘vertical and horizontal integration’, which is a key tenet of systems thinking. The integration-in-totality principle is illustrated and elucidated with the help of a simple “Rubik’s cube model of integration-in-totality principle” with three orthogonal axes, the ‘axis of perspective’ of vertical integration, and the two ‘axes of perception and performance’ of horizontal integration. Safety analysis along the three axes with a ‘bidirectional synthesis’ and ‘continuum approach’ is further elaborated with relevant case studies, one among them related to the Boeing 737 MAX aircraft twin disasters. Safety is directly linked to quality, reliability and risk, through a self-reinforcing reflexive paradigm, and airworthiness assurance is the process through which safety concepts are embedded in a multidisciplinary aviation environment where the system of systems is seamlessly operating. The article explains how the system safety principle of integration-in-totality is related to reliability and airworthiness of an aerospace system with the help of the ‘V-model of systems engineering’. The article also establishes the linkage between integration-in-totality principle and strategic quality management, thus bridging the gap between two parallel fields of knowledge.