Background <p>Protein undernutrition (PU) plays a vital role in the structural and biochemical abnormalities in the different brain regions and the development of liver diseases.</p> Purpose <p>The study investigated the therapeutic potential of fish oil (FO) in low-protein diet-induced oxidative stress in the brain and liver, as well as lipid dyshomeostasis in rats.</p> Methods <p>The rats were randomly assigned to four groups, and the normal-protein diet (NPD) and NPD-treated (NPDT) rats, having six rats per group, were fed with 16% casein diet, and the LPD and LPD-treated (LPDT), having eight rats per group, were fed with 5% casein diet. After the 8th week, FO (400&#xa0;mg/Kg b.w.t) was given orally for 21&#xa0;days.</p> Results <p>A significant reduction was observed in the growth of LPD-fed rats compared to the NPD-fed rats. The lipid peroxidation (LPO) level was significantly higher, whereas GSH level and SOD and GPx activities were significantly reduced in both tissues of LPD rats. CAT and AChE activities decreased considerably in the cerebellum. In addition, CHOL, VLDL, and TG levels were significantly increased in LPD-fed rats. FO treatment did not affect the growth except at week 10 but became normalized at week 11. In LPDT rats, FO significantly reduced the LPO, but it increased GSH level and GPx activity in both tissues while CAT and AChE activities increased in the cerebellum. Also, FO treatment increased SOD activity in the liver but decreased CHOL, LDL, VLDL, and TG levels in the LPDT group.</p> Conclusion <p>FO may effectively protect against hepatic oxidative stress, cerebellar functions, and lipid homeostasis in low-protein-fed rats.</p>