Activated Akt and ERK signaling pathways are closely related to breast cancer progression, and Akt or ERK inhibition induces cell senescence. However, the crosstalk between the Akt and ERK signaling pathways in cell senescence and how to simultaneously suppress Akt and ERK signaling in triple-negative breast cancer (TNBC) are undefined. In this study, we found that norcantharidin (NCTD) effectively induced cell senescence and cell cycle arrest in TNBC in vitro, which was accompanied by a decline in phosphorylated Akt and ERK1/2 and a rise in p21 and p16. The inhibitors LY294002 and U0126 imitated the effect of NCTD when these two inhibitors were combined regardless of crosstalk between these two signaling pathways. In addition, NCTD inhibited the growth of xenografts via downregulation of phosphorylated Akt and ERK1/2 and upregulation of p21 in vivo. However, NCTD upregulated the level of soluble signaling factors of the senescence-associated secretory phenotype (SASP) in a NF-κB-independent manner. Collectively, these findings demonstrate that NCTD induced cell senescence and cell cycle arrest mainly by simultaneously blocking Akt and ERK signaling in TNBC, suggesting that NCTD may be used as a potential adjuvant therapy in TNBC.