Foods and animal feeds frequently become contaminated with the nephrotoxic ochratoxin A (OTA). Our prior research has indicated that ursolic acid (UA), which is widely present in fruits and medicinal plants, has the potential to alleviate nephrotoxicity triggered by OTA. Additionally, excessive induction of endoplasmic reticulum (ER)-phagy exacerbates OTA-induced apoptosis. Therefore, further investigation is essential to comprehend whether UA can mitigate OTA-induced apoptosis by influencing ER-phagy. This objective is accomplished through a series of experiments involving assessments of cell viability, apoptosis, fluorescence microscopy, and western blot analysis. The outcomes of these experiments reveal that pre-treatment with 4 μmol/L UA for 2 h can markedly reverse the elevated apoptotic rate, the co-localization of ER and lysosomes, and the protein expressions of GRP78, p-eIF2α, Chop, Bax, and Bak, as well as the reduced cell viability and the protein expressions of Lonp1, Trap1, p62, Tex264, FAM134B, Bcl-2, and Bcl-xl, all caused by exposure to 1 μmol/L OTA for 24 h in human proximal tubule epithelial-originated kidney-2 (HK-2) cells (P < 0.05). Interestingly, the increased expression of LC3B-II induced by OTA is further amplified by UA pre-treatment (P < 0.05). In conclusion, OTA triggers a harmful feedback loop between ER stress (ERS) and excessive ER-phagy, thereby further promoting ERS- and mitochondrial-mediated apoptosis in vitro. However, this effect is significantly mitigated by UA through the inhibition of autophagosome-lysosome fusion, consequently blocking the excessive ER-phagic flux.