Studying the dynamic role of microglia in brain development and neurodegenerative diseases requires models that closely resemble the human brain environment. While murine models provide valuable insights, they often have important transcriptional and cellular differences from humans. Addressing this, we developed a chimeric in vitro model to study microglial behavior within a human-like neuronal setting.We co-cultured human iPSC-derived human organoids (hORG) with mouse brain slice cultures (mBSC). In this chimeric setup we found multiple interactions between mouse and human tissue, markedly accelerating organoid maturation. Notably, we observed the extension of axons from human neurons toward the mBSC and the migration of mouse astrocytes toward the hORG, indicating a profound integration of human and mouse neural components.A central discovery in our research was the robust migration of human iPSC-derived microglia—differentiated in the mBSC following the depletion of endogenous mouse microglia—into the hORG soon after initiating co-culture. This dynamic migration process, coupled with a transition from an activated to a ramified morphology, signifies microglia functional maturation within this chimeric setting. Notably, microglia also effectively responded to focal laser-induced injuries, mirroring in vivo human microglial functions and underscoring the model's capacity to emulate complex microglial behavior.The chimeric model marks a significant advancement in microglia research that will enable detailed exploration of neurodegenerative diseases. Its potential to foster human microglial differentiation and accurately replicate in vivo conditions underscores its pivotal role in advancing our understanding of microglial functions in health and disease.