Chromatin modifiers regulate genome function by modulating chromatin structure and are essential for processes such as transcription, DNA repair, and cell division. The lysine acetyltransferase TIP60 (KAT5), a member of the MYST family, is a key regulator of chromatin dynamics and has established roles in stem cell maintenance and differentiation, however its function in regeneration remains unclear. Here, we investigated the role of the TIP60 homolog (SMED-TIP60) in the planarian Schmidtea mediterranea, a model system for stem cell-driven regeneration. Biochemical analyses demonstrated that SMED-TIP60 possesses both histone acetyltransferase and autoacetylation activities. Functional depletion of Smed-tip60 by RNA interference impaired tissue homeostasis and survival. Regeneration assays revealed severe defects in blastema formation, culminating in a complete failure of regeneration upon TIP60 loss. Mechanistically, in situ hybridization and immunofluorescence analyses showed a marked reduction in stem cell populations and proliferation in Smed-tip60 RNAi animals. Injury-induced expression of SMED-TIP60 peaked at 5 days post-amputation, and transcriptomic (RNA-seq) analysis revealed widespread dysregulation of gene expression at both anterior and posterior wound sites, with increased transcriptional perturbation correlating with elevated TIP60 levels. Furthermore, key wound-response genes were aberrantly expressed in Smed-tip60-depleted animals, indicating disruption of the injury-response program and positional information resetting. Collectively, these findings identify TIP60 as an essential regulator of stem cell-mediated regeneration, functioning to coordinate wound-response gene expression and tissue restoration.