LCL161 is a second mitochondrial activator of caspases (SMAC) mimetic and inhibitor of apoptosis protein (IAP) antagonist that has oral bioavailability, exhibits anti-tumor effects and improves the chemical sensitivity of many cancers. The aim of this study was to ascertain the effects and mechanisms of the SMAC analog LCL161 on breast cancer drug-resistant cells after undergoing caspase inhibition. This was achieved through use of colony formation and CCK-8 assays to detect cell proliferation. Flow cytometry, Western blot analysis, ATP assay, immunofluorescence and siRNA transfection were used to study the molecular mechanisms of LCL161-induced death of cisplatin-resistant MCF-7 cells after caspase inhibition. LCL161 exhibited an inhibitory effect on MCF-7/DDP cells including after inhibition of caspase. However, LCL161 could not on its own induce a necroptosis effect on MCF-7/DDP cells (P < 0.01 or P < 0.001). When used jointly with the caspase inhibitor z-VAD-fmk, it significantly decreased intracellular ATP levels (P < 0.01 or P < 0.05). This induction of necroptosis occurred through the activation of the RIP1-RIP3-MLKL programmed cell necrosis cascade. Knockdown of RIP3 using siRNA protected against the combined LCL161 / z-VAD-fmk-induced cell death (P < 0.01 or P < 0.001). These findings support the hypothesis that LCL161 combined with caspase inhibition can induce a necroptosis effect on MCF-7/DDP cells, suggesting that it has potential to be an effective treatment for breast cancer.