Breakdown of intestinal barrier integrity can lead to immune-mediated pathologies such as Inflammatory bowel disease (IBD). Although promoting intestinal regeneration has emerged as a promising alternative to treat IBD, its therapeutical implementation has not yet been achieved due to 1) the lack of relevant screening systems mimicking what occurs in vivo, and 2) a deficient understanding of the mechanisms governing intestinal regeneration. To fill this gap, we generated a zebrafish model of controlled and targeted intestinal epithelial cell (IEC) ablation to study the mechanisms of intestinal regeneration. By combining live imaging, scRNAseq, and functional experiments, we identified macrophages as contributors to intestinal regeneration. Furthermore, we found overexpression of igfbp1a in IECs, which was protective to Mtz-induced death. In summary, we provide a new in vivo model, compatible with high-throughput screenings, to identify and validate novel modulators of intestinal regeneration, opening new therapeutical avenues to treat IBD.