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Cu is a metallic element that widely spread over in the environment, which have raised wide concerns about the potential toxic effects and public health threat. The objective of this study aimed to investigate the impression of copper (Cu)-triggered toxicity on mitochondrial dynamic, oxidative stress, and unfolded protein response (UPRmt) in fundic gland of pigs. Weaned pigs were randomly distributed into three groups, fed with different Cu of 10 mg/kg (control group), 125 mg/kg (group I), and 250 mg/kg (group Ⅱ). The trial persisted for 80 days and the fundic gland tissues were collected for further researches. Moreover, the markers participated to mitochondrial dynamic, UPRmt，and oxidative stress in fundic gland were determined. Results revealed that vacuolar degeneration were observed in the treated groups contrast with control group, and the Cu level was boosted with the increasing intake of Cu. Besides that, the levels of CAT, TRX, H 2 O 2 , and G 6 PDH were reduced in group Ⅰ and group Ⅱ, the mRNA levels of NRF2 , HO-1 , SOD-1 , CAT , SOD-2 , GSR , GPX1 , GPX4 , and TRX in the treated groups were promoted contrast to control group. Furthermore, the protein expression of KEAP1 was dramatically decreased, and the protein expression of NRF2 , TRX and HO-1 were markedly enhanced in group Ⅰ and Ⅱ at 80 days. Moreover, the mRNA and protein expression levels of MFN1 , MFN2 , and OPA1 down-regulated and protein level of DRP1 was increased with the adding levels of Cu. Nevertheless, the UPRmt-related mRNA levels of CLPP , HTRA-2 , CHOP , HSP10 , and HSP60 were enhanced dramatically in Cu treatment group compared with control group. In general, our current study demonstrated that excessive absorption of Cu in fundic gland were related with stimulating UPRmt, oxidative stress, and the NRF2 interceded antioxidant defense. These results could afford an updated evidence on molecular theory of Cu-invited toxicity. [Display omitted] • Copper exposure induced fundic gland toxicity. • Copper triggers the NRF2-mediated antioxidant defense. • Copper induced mitochondrial damaged via inhibition of UPRmt. [ABSTRACT FROM AUTHOR]