Ibuprofen (IBU), a prevalent non-steroidal anti-inflammatory drug (NSAID), is extensively utilized in medical practices. Especially since the popularity of COVID-19, its use has become more widespread, coupled with its low degradation rate and high environmental residues. Thus, more focus is warranted on the possible detrimental impacts on non-target organisms, as well as the underlying mechanisms of toxicity. The present study investigated the relationships and molecular mechanisms between hepatic mitochondrial dynamics processes and lipid metabolism in the yellowstripe goby (Mugilogobius chulae) exposed to IBU at concentrations of 0.5, 5, 50, and 500 μg/L over 7 days. The results showed that IBU exposure inhibited mitochondrial biogenesis and fusion but promoted mitochondrial fission by interfering with the SESN/PGC/ULK signaling pathway, causing an imbalance in mitochondrial dynamics. Thus, high concentration of IBU exposure caused mitochondrial dysfunction and oxidative stress. Molecular biological evidences suggested that IBU caused a decrease in ATP production and lipogenesis, leading to an energetic crisis in M. chulae. Hepatic tissue also showed a significant decrease in relative weight, an increase in mitochondrial damage and adipocyte degeneration. Correspondingly, the exposed organism attempted to mitigate these crises by promoting mitophagy and lipophagy via the Pink-Parkin pathway. Overall, IBU exposure interfered with mitochondrial dynamics processes and caused abnormalities in hepatic lipid metabolism in M. chulae. The present study highlighted the discovery of mitochondrial dynamics imbalance to lipid dysregulation cascade mechanism. We emphasized the negative effects of NSAIDs such as IBU on aquatic non-target organisms at different levels. It provided valuable insights into the ecological risk assessment of IBU in aquatic environments.