Human bone marrow-derived mesenchymal stem cells (MSCs) are currently widely used in cell therapy and tissue engineering. In vitro experiments have demonstrated that apoptosis of MSCs can be induced by hypoxia, serum deprivation, and chemotherapeutic agents, and the process is p53 independent. In this study, we investigated the role of p63 (a member of p53 family) in the regulation of apoptosis of MSCs. TAp63α, a subtype of p63, is highly similar to p53 and plays a crucial role in apoptosis. In vitro exposure of MSCs to either cisplatin or etoposide resulted in an increased TAp63α expression, which was time and dose dependent. Interference of TAp63α led to drug resistance and decreased apoptosis, accompanied by reduced expression of Bax, poly(ADP-ribose) polymerase, and caspase-3. However, downregulation of TAp63α did not influence the phenotype, proliferation capacity, and differentiation potential of MSCs. These results indicate that downregulation of TAp63α in MSCs is an attractive strategy to protect against apoptosis when MSCs are used to support hematopoiesis during bone marrow transplantation.