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Berberine acts via multiple pathways to alleviate fibrosis in various tissues and shows renoprotective effects. However, its role and underlying mechanisms in renal fibrosis remain unclear. Herein, we aimed to investigate the protective effects and molecular mechanisms of berberine against unilateral ureteric obstruction‐induced renal fibrosis. The results indicated that berberine treatment (50 mg/kg/day) markedly alleviated histopathological alterations, collagen deposition and inflammatory cell infiltration in kidney tissue and restored mouse renal function. Mechanistically, berberine intervention inhibited NOD‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome activation and the levels of the inflammatory cytokine IL‐1β in the kidneys of unilateral ureteric obstruction mice. In addition, berberine relieved unilateral ureteric obstruction‐induced renal injury by activating adenosine monophosphate‐activated protein kinase (AMPK) signalling and promoting fatty acid β‐oxidation. In vitro models showed that berberine treatment prevented the TGF‐β1‐induced profibrotic phenotype of hexokinase 2 (HK‐2) cells, characterized by loss of an epithelial phenotype (alpha smooth muscle actin [α‐SMA]) and acquisition of mesenchymal marker expression (E‐cadherin), by restoring abnormal fatty acid β‐oxidation and upregulating the expression of the fatty acid β‐oxidation related‐key enzymes or regulators (phosphorylated‐AMPK, peroxisome proliferator activated receptor alpha [PPARα] and carnitine palmitoyltransferase 1A [CPT1A]). Collectively, berberine alleviated renal fibrosis by inhibiting NLRP3 inflammasome activation and protected tubular epithelial cells by reversing defective fatty acid β‐oxidation. Our findings might be exploited clinically to provide a potential novel therapeutic strategy for renal fibrosis. [ABSTRACT FROM AUTHOR]