Pheochromocytomas and paragangliomas (PCPGs) are catecholamine-producing neuroendocrine tumors. Accumulating evidences indicate that the blockade of antioxidative pathways might be a novel therapeutic approach to the treatment of PCPG. NIX has been confirmed to play a key role in maintaining redox homeostasis in tumors, while the function of NIX in PCPG remains unclear. In this study, the analyses of the disease-free survival (DFS) showed that high NIX protein level is related to poor prognosis in patients of PCPG. Consistent with this, high level of NIX protein upregulates the level of p-NF-κB and promotes the migration of PC12 cells. In NIX-over-expressing PC12 cells, the level of reactive oxygen species (ROS) is decreased while trolox-equivalent antioxidant capacity (TEAC) increased. But in NIX-silencing cells, ROS level is increased, while TEAC reversely reduced, consequently antioxidase and phase II enzymes of NRF2 signaling were activated, and elevated endoplasmic reticulum (ER) stress was observed. Additionally, the apoptosis induced by luminespib/NVP-AUY922, an inhibitor of heat shock protein 90 (HSP90, a cellular stress response factor), was enhanced in NIX-silencing cells but reduced in the NIX-over-expressing cells. All of these results indicated that high NIX protein level enhances antioxidant capacity of PC12 cells and reduces the apoptosis caused by cell stress, such as induced by luminespib/NVP-AUY922. Therefore, luminespib/NVP-AUY922 might be effective only for PCPG with low NIX level, while targeting NIX could be a further supplement to the therapeutic treatment strategy for PCPG patients with high NIX protein level.