Polyunsaturated fatty acids (PUFAs) regulate renal inflammation through metabolites generated by COX, LOX, and CYP pathways. While prostaglandins, leukotrienes, and 20-hydroxyeicosatetraenoic acid (20-HETE) exacerbate kidney injury, epoxyeicosatrienoic acids (EETs), lipoxins, and other specialized pro-resolving mediators (SPMs) counteract inflammation and promote tissue repair. These lipid mediators also modulate nuclear receptors such as peroxisome proliferator-activated receptors (PPARs) and fibrotic pathways like TGF-β signaling. Disease-specific imbalances in PUFA metabolism have been implicated in nephrotic syndrome, glomerulonephritis, kidney transplantation, and renal cancer. This review integrates mechanistic insights with experimental and clinical data, highlighting therapeutic strategies including dietary ω-3 PUFA supplementation, synthetic SPM analogs, selective enzyme inhibitors, and nanocarrier-based delivery systems. We also address limitations, such as short half-life, off-target effects, and immunoregulatory risks. Lipidomic profiling may aid in patient stratification and treatment personalization. Collectively, targeting PUFA-derived lipid mediators offers a promising adjunct to conventional therapies for inflammatory and immune-mediated kidney diseases.

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