Acute kidney injury (AKI) causes a lot of harm to human health but is treated by only supportive therapy in most cases. Recent evidence shows that mesenchymal stem cells (MSCs) benefit kidney regeneration through releasing paracrine factors and extracellular vesicles (EVs) to the recipient kidney cells and are considered to be promising cellular therapy for AKI. To develop more efficient, precise therapies for AKI, we review the therapeutic mechanism of MSCs and MSC-derived EVs in AKI and look for a better understanding of molecular signaling and cellular communication between donor MSCs and recipient kidney cells. We also review recent clinical trials of MSC-EVs in AKI. This review summarizes the molecular mechanisms of MSCs’ therapeutic effects on kidney regeneration, expecting to comprehensively facilitate future clinical application for treating AKI.