In recent years, data-driven inference of cell-cell communication has helped reveal coordinated biological processes across cell types. While multiple cell-cell communication tools exist, results are specific to the tool of choice, due to the diverse assumptions made across computational frameworks. Moreover, tools are often limited to analyzing single samples or to performing pairwise comparisons. As experimental design complexity and sample numbers continue to increase in single-cell datasets, so does the need for generalizable methods to decipher cell-cell communication in such scenarios. Here, we integrate two tools, LIANA and Tensor-cell2cell, which combined can deploy multiple existing methods and resources, to enable the robust and flexible identification of cell-cell communication programs across multiple samples. In this protocol, we show how the integration of our tools facilitates the choice of method to infer cell-cell communication and subsequently perform an unsupervised deconvolution to obtain and summarize biological insights. We explain how to perform the analysis step-by-step in both Python and R, and we provide online tutorials with detailed instructions available at https://ccc-protocols.readthedocs.io/. This protocol typically takes ~1.5h to complete from installation to downstream visualizations on a GPU-enabled computer, for a dataset of ~63k cells, 10 cell types, and 12 samples.