Renal tubular injury is the hallmark of cisplatin-induced nephrotoxicity. Caspase-11, a member of the caspase family, plays an important role in inflammation and cell death. However, its role in cisplatin-induced renal tubular injury remain unclear. We observed that caspase-11 expression was significantly elevated and the expression of caspase-11 mainly located in renal tubule in cisplatin-treated mice. Inhibition of caspase-11 by siRNA or wedelolactone (Wed) attenuated cisplatin-induced renal dysfunction and tubular injury. In primary renal tubular epithelial cells, cisplatin significantly promoted the expression and activation of caspase-11. Inhibition of caspase-11 by siRNA reduced cisplatin-induced cell apoptosis. Overexpression of caspase-11 promoted cell apoptosis by activating caspase-3-related apoptotic pathway. Furthermore, Co-immunoprecipitation results showed there was a direct interaction between caspase-11 and caspase-3. The fluorescence confocal microscopy results showed that caspase-11 and caspase-3 were co-localized in the cytoplasm of primary renal tubular epithelial cells. These results demonstrate that caspase-11 plays an important role in cisplatin-induced renal tubular injury. Caspase-11 promotes renal epithelial cell apoptosis by activating caspase-3-dependent apoptotic pathway. Caspase-11 may be a potential target for therapeutics against cisplatin-induced nephrotoxicity.