Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. TBI’s mechanism is complex, but it may involve a particular type of cell death called pyroptosis, especially among brain cells known as microglia. Mesenchymal stem cells (MSCs), such as the stem cells in umbilical cords, have recently been found to regulate pyroptosis, but it’s unclear whether transplanted MSCs could help alleviate pyroptosis after TBI. To find out, researchers recently administered human umbilical cord MSCs and the MSC-secreted protein TSG-6 into the brains of mice with induced TBI. Both the MSCs and the TSG-6 protein alleviated neurological deficits in the TBI mice. They also reduced inflammatory molecule expression and inhibited microglial pyroptosis in the cerebral cortex. The MSCs’ beneficial effects were weakened when TSG-6 expression was inhibited, confirming the importance of this molecule. In addition, the MSCs and TSG-6 inhibited pyroptosis in a microglial cell line in vitro, which verified the in vivo effects. Although studies in humans are needed, the results reveal how MSCs can help reduce microglial cell death after TBI and suggest that stem cell transplantation is a promising strategy for healing the brain after TBI.