INTRODUCTION: Leigh syndrome is often caused by Ndufs4 mutations. The Ndufs4 knockout (KO) mouse model recapitulates key disease features, including systemic inflammation, neurodegeneration, and motor deficits. While dietary interventions such as the ketogenic diet show promise in mitigating mitochondrial dysfunction, conflicting results highlight uncertainties regarding its efficacy. Here, we evaluate the therapeutic potential of a polyunsaturated fatty acid (PUFA)-enriched high-fat diet (HFD) in Ndufs4 KO mice. METHODS: Dietary intervention began at postnatal day 23, with mice receiving either a normal diet (ND) or a HFD enriched with PUFAs. Phenotypic evaluation, including locomotor function, clasping behaviour, and survival, continued until natural death. In a second group of animals, biochemical analyses were conducted after three weeks on the diets, using Western blot to evaluate neurometabolic and inflammatory regulators, flow cytometry to quantify serum inflammation markers, and metabolic profiling to identify alterations in neurometabolism and the neurolipidome. RESULTS: The HFD significantly extended lifespan and improved clasping behaviour in Ndufs4 KO mice but had no effect on locomotor activity or grip strength decline. While whole-brain mTOR (p70S6K1, 4E-BP1) and SIRT1 (PGC1-α, TNF-α) signalling pathways remained unaffected, the diet significantly reduced serum pro-inflammatory markers TNF and IL-6. Furthermore, the PUFA-enriched HFD partially restored disruptions in TCA cycle, ketone body, branched-chain amino acid, and lipid metabolism, indicating potential metabolic reprogramming. CONCLUSION: Dietary interventions, such as a PUFA-enriched HFD, may alleviate systemic inflammation, partially correct metabolic imbalances, and mitigate specific disease phenotypes in Leigh syndrome, warranting further investigation into the underlying mechanisms and broader therapeutic applications.