Polybrominated diphenyl ethers (PBDEs) exist in aquatic environments with nephrotoxicity to non-target aquatic species. Melatonin (MT) exhibits an inhibitory effect of oxidative stress and apoptosis in various diseases. 2, 2′, 4, 4′-tetrabromodiphenyl ether (BDE-47) is the main homolog of PBDE samples. Therefore, we investigated the toxic mechanism of BDE-47 and the alleviation effect of MT, the ctenopharyngodon idellus kidney (CIK) cells were treated with BDE-47 (100 μM) and/or MT (60 μM) for 24 h. Firstly, BDE-47 exposure could inhibit oxidative stress-related antioxidant enzymes (T-AOC, SOD, CAT and GPx) and increase the content of malondialdehyde (MDA) to cause oxidative stress. Secondly, BDE-47 enhanced mitochondrial division and inhibited fusion to induce mitochondrial membrane potential in CIK cells. BDE-47 enhanced the mRNA and protein levels of mitochondrial-pathway apoptosis related genes (Cas 3, Cyt-c, and BAX). Thirdly, BDE-47 treatment decreased the expression levels of mitochondrial-related regulatory factors AMPK-Sirt1-PGC-1α signal pathway. Intriguingly, BDE-47-induced oxidative stress, mitochondrial pathway apoptosis and mitochondrial dynamics disorder could be alleviated by MT treatment. Overall, we concluded that MT could relieve BDE-47-induced oxidative stress, mitochondrial dysfunction and apoptosis through the AMPK-Sirt1-PGC-1α axis. These results enrich the mechanisms of BDE-47 poisoning and reveal that MT treatment may be a potential strategy for solving BDE-47 poisoning.