Infrastructure systems are subjected to demands imposed by extreme natural events and increasing socioeconomic pressures. The latter are derived, for example, from a rise in the export of goods and services, and population growth, which is also associated with problems such as access to housing and basic sanitation. According to the World Risk Report 2016, inadequate infrastructure increases the frequency of losses to life and property, as well as the risk that an extreme natural event might become a disaster. Thus, frequently, traditional infrastructure systems design and management have fail to meet the stakeholders’ expectations. The main problems emerge from decisions based on the assumption that systems are static, instead of changing continuously, and on uncertainty management. This paper presents, first, a conceptual proposal that combines systems thinking and flexibility as the main pillars to facilitate systems to respond and change over time. Systems thinking recognizes the dynamic evolution of systems and helps understand how processes and subprocesses interact at different levels (i.e., hierarchical arrangement of processes). Flexibility, which is the ability of a system to respond or change, is crucial to managing better risks and varying demands, thus fostering resilience to disasters and climate change. Incorporating flexibility in the development of infrastructure contributes to enhancing the management of planned or unplanned events, taking advantage of investment/business opportunities, reducing possible cost overruns, and handling the perceptions and interests of stakeholders. Based on the conceptual framework, the second part of the paper presents a proposal to integrate these concepts into a physical and financial infrastructure model. The outcome of this model is a set of management policies that render the actions that best reflect the interest of stakeholders. The conceptual ideas and the proposed model are illustrated with two examples showing the value of integrating systems thinking and flexibility in infrastructure management over time.