The purpose of this paper is to present a quantitative methodology for managing sustainability in response to major disruptions in complex supply chains. Sustainable enterprise management can be understood as a decision-making process looking to simultaneously achieve goals on the three dimensions of sustainability (economic, social and environmental). Inspired by globalized supply chains, which are prone to high levels of turbulence and uncertainty, our model is generic enough to evaluate performance metrics and does contribute to enhanced risks and vulnerability management in the supply chain. This paper presents a formal methodology to measure the impact of operational decisions when major disruptions (e.g., natural disasters) affect the defined design of a supply chain. Such proposed methodology is based on the coupling of optimization (e.g., mathematical programming) and discrete-event simulation. The approach is validated using numerical examples. Hence, one of the contributions of this paper is the development of a combined measure of sustainable responsive performance within a global supply chain context.