The Sichuan–Tibet Railway is facing extraordinary challenges in terms of construction, operation, and maintenance because of its extremely complicated natural environment and geological conditions. Consequently, countermeasures are necessary and urgent to ensure its safety and reliability in the whole life cycle. This study proposes a novel reliability framework to guarantee the ideal operation state of the Sichuan–Tibet Railway. Reliability application in many fields are summarized, including military equipment, rail locomotive, and railway engineering. Given the fact that the Sichuan–Tibet Railway is a complex giant system, Nine-Connotation was summarized (i.e., safety, inherent reliability, testability, maintainability, supportability, environmental adaptability, predictability, resilience, and durability) under the goal of optimizing the operational efficiency. On the basis of the concept of the Nine-Connotation and the understanding of reliability transmission mechanism, the framework of reliability for the Sichuan–Tibet Railway was established, which can facilitate a comprehensive and real-time evaluation of all situations with a clear hierarchy. The proposed framework is composed of a resilience management system, an integrated technology system, and a dynamic reliability assessment system. The pathway for its application on railway construction was developed in this study. The proposed framework can assist in well-informed decisions for the construction, as well as the operation of the Sichuan–Tibet Railway. On the basis of a top–down design concept for the first time, this study emphasizes the railway’s availability and validity to complete the assigned tasks as a whole, that is, operational efficiency. It also shows the reliability transmission and control mechanism of the railway’s giant complex system, innovating and establishing the management principle of great safety and great reliability over the life cycle.