The conventional single-agent approach to therapeutics is challenged by the redundancy and feedback in biological networks. The use of multiple drugs in combination might improve desired functional outcomes while reducing toxicity and overcoming drug resistance. However, the complexity and resources required to test many combinations have slowed discovery efforts. Here, we introduce a screening platform that automatically constructs combinations of drugs from nanoliter-scale droplets, greatly simplifying screening logistics and reducing resource consumption. We applied our platform to discover drug pairs that act synergistically against the model pathogen Escherichia coli . Our platform can be further developed to support many types of phenotypic assays in a variety of disease models.