BACE1, a key protein involved in Alzheimer's progression, initiates Aβ42 generation that induce senile plaques in brain. However, the role of chaperone synergy or antagonism on BACE1‐mediated amyloid processing is unknown. We have discovered that BACE1 as well as Aβ42 are antagonistically controlled by ER chaperone ORP150 and cellular chaperone CHIP. We have shown ORP150 as a chaperone interacts with and stabilizes BACE1 at post‐translational level. Furthermore, ORP150 enhances BACE1‐mediated amyloid processing thus masking CHIP‐mediated BACE1 degradation. Conversely, siORP150 reversed the chaperone function of ORP150 resulting in BACE1 degradation. ORP150 and CHIP demonstrate antagonism under normal and stress conditions wherein they inversely regulate each other thus affecting BACE1 level. In conclusion, we have uncovered for the first time a phenomenon of chaperone antagonism on BACE1‐mediated Aβ42 generation. Future strategy would require both suppression of ORP150 as well as activation of E3‐ligase activity of CHIP that might prevent Aβ42 in Alzheimer's disease. Our study for the first time shows a new chaperone antagonism phenomenon between ORP150 and CHIP in regard to BACE1 stability and Aβ formation. Future strategy would be to develop therapeutics in suppressing chaperone function of ORP150 as well as activation of CHIP in destabilizing BACE1 and in order to prevent Aβ42 level in AD patients.