Prompt and efficient intervention is vital in reducing casualty figures during epidemic outbreaks, disasters, sudden civil strife or terrorism attacks. This can only be achieved if there is a fit-for-purpose and location-specific emergency response plan in place, incorporating geographical, time and vehicular capacity constraints. In this research, a comprehensive emergency response model for situations of uncertainties (in locations' demand and available resources), typically obtainable in low-resource countries, is designed. It involves the development of algorithms for optimizing pre-and post-disaster activities. The studies result in the development of four models: (1) an adaptation of a machine learning clustering algorithm, for pre-positioning depots and emergency operation centers, which optimizes the placement of these depots, such that the largest geographical location is covered, and the maximum number of individuals reached, with minimal facility cost; (2) an optimization algorithm for routing relief distribution, using heterogenous fleets of vehicle, with considerations for uncertainties in humanitarian supplies; (3) a genetic algorithm-based route improvement model; and (4) a model for integrating possible new locations into the routing network, in real-time, using emergency severity ranking, with a high priority on the most-vulnerable population. The clustering approach to solving dept location-allocation problem produces a better time complexity, and the benchmarking of the routing algorithm with existing approaches, results in competitive outcomes.