Multicellular animals arose along with complex gene programs controlling tissue integrity. A comprehensive understanding of the core mechanisms underlying tissue maintenance in metazoans requires studying early-branching animal groups. Here, we present whole-body regeneration (reaggregation from single cells) in sponges as a promising model for exploring conserved mechanisms maintaining tissue homeostasis in Metazoa. Using bulk RNA sequencing, we linked differential expression to major morphological changes in tissue and cell structure following the mechanical dissociation of intact tissues of a demosponge, Halisarca dujardinii. Reaggregation involves a pronounced shift in the expression of transcripts related to cell adhesion, cell polarity, proliferation, and stem cell maintenance. Cell cycle machinery is underexpressed during the reaggregation, whereas programs of stem cell maintenance and epithelial–mesenchymal transition (EMT) are upregulated. Altogether, the expression profiles render reaggregation a morphallactic reparative process driven primarily by cell plasticity rather than cell proliferation.