The concept of water security has been widely implemented in regional, national, and global contexts in recent years. Urban water security encapsulates water resource availability, equitable access, environmental sustainability, and safety from water-related disasters. Megacities around the globe, particularly in the developing world, have been encountering environmental challenges due to changing climate, rapid urbanisation, and accelerated population growth. In this paper, we develop and implement a framework for holistic water security assessment at the city level in the context of extreme events. The framework entails defining dimensions and their respective indicators and subsequently measuring those indicators using several variables to calculate the Water Security Index using a nexus approach. These indicators and their respective variables (sub-indicators) were selected based on the drivers, pressures, states, impacts, and responses (DPSIR) influencing urban water security in a mega city. The water supply dimension represents the quality, quantity, and access to potable water, whereas the water governance dimension refers to the administrative system as well as consumer awareness and support for water conservation. A city’s susceptibility to floods, droughts, cyclones, and the mitigation interventions is quantified in the water-related disasters dimension. The water environment represents the environmental needs of water and the pollution status of natural water bodies, and the water economy dimension relates to the economic aspects of urban water. Lastly, the sanitation and hygiene dimension measure the current state of overall hygiene and citizens’ health. The developed framework is then applied to assess the water security of a megacity using Karachi as a case study.