BACKGROUND: Acute kidney injury (AKI) is a common complication of cardiac surgery. Human umbilical cord mesenchymal stem cell (hUCMSC)-derived exosomes affect tissue damage and repair, and miR-21-5p reduces apoptosis and inflammation. However, miR-21-5p's role in cardiac surgery remains unclear. METHODS: Kidney injury molecule (KIM-1), neutrophil gelatinase-associated lipid carrier protein (NGAL), serum creatinine, and blood urea nitrogen (BUN) levels were tested by enzyme-linked immunosorbent assay. hUCMSCs and exosomes were identified via Oil Red O staining kit, alkaline phosphatase staining kit, flow cytometry, transmission electron microscopy, Western blot, and immunofluorescence. Cell viability and apoptosis were detected by cell counting kit 8 and flow cytometry. Interleukin-1β, interleukin-6, and tumor necrosis factor-alpha levels were tested by ELISA kits. Relativity between miR-21-5p and TEA domain family member 1 (TEAD1) was verified by dual-luciferase reporter gene assay and western blot. TEAD1, BUN, and creatinine levels in vivo were tested via immunohistochemistry and automatic biochemistry analyzer. RESULTS: KIM-1, NGAL, serum creatinine, and BUN levels were increased and miR-21-5p expression was inhibited in AKI after cardiac surgery. In AKI after cardiac surgery, hUCMSCs-Exos inhibited apoptosis and pyroptosis and promoted viability via miR-21-5p regulation. hUCMSCs-Exos retarded AKI after cardiac surgery progression by facilitating miR-21-5p targeting of TEAD1. hUCMSCs-Exos promoted miR-21-5p and inhibited TEAD1 expression in vivo. miR-21-5p knockdown facilitated TEAD1 expression in vivo. Results were exactly the same in vivo and in vitro AKI models. CONCLUSIONS: hUCMSCs-Exos protect against AKI by enhancing miR-21-5p/TEAD1 binding in vivo and in vitro.