ABSTRACT: Potato, the most important non-cereal crop, is highly water and space efficient but susceptible to abiotic stress such as heat, drought, or flooding. Due to climate change the likelihood of such stresses to occur, individually, sequentially, or simultaneously, has dramatically increased. While we have detailed insights into plant responses to single stresses in some model plants, the understanding of acclimation to multiple abiotic stresses in crops is still very limited. Here we present a comprehensive molecular and physiological profiling of potato (Solanum tuberosum, cv. Desirée) under both single and multiple abiotic stresses (heat, drought, and waterlogging), designed to mimic realistic future scenarios. Daily phenomics analysis enabled monitoring of the acclimation responses over time. In parallel, leaf samples were taken throughout the 28-day experiment for multi-omics analysis including transcriptomics, metabolomics, proteomics, and hormonomics. At the end of the period, critical metabolites of tuber samples were analysed. To facilitate the multi-omics analyses, the dataset was integrated with expert knowledge, an approach that is increasingly necessitated in the development of high-throughput pipelines in agricultural research. Waterlogging had immediate and most dramatic effects, and surprisingly, the responses were similar to drought stress. In contrast, distinct stress signatures at morpho-physiological, metabolic, and molecular levels were found in response to heat or drought stress and to a combination of both.