The ketogenic diet (KD), a high-fat and extremely low-carbohydrate dietary regimen, has long been acknowledged as a highly beneficial dietary therapy for the treatment of intractable epilepsy throughout the last decade. Because of its significant therapeutic potential for a variety of ailments, KD is increasingly attracting study interest. In renal fibrosis, KD has received little attention. This study aimed to determine whether KD protects against renal fibrosis in unilateral ureteral obstruction (UUO) models and the possible mechanisms. The ketogenic diet, according to our findings, reduces UUO-induced kidney injury and fibrosis in mice. KD dramatically decreased the number of F4/80+macrophages in kidneys. Next, immunofluorescence results revealed a reduction in the number of F4/80+Ki67+macrophages in the KD group. Furthermore, our study evaluated the impact of β-hydroxybutyric acid (β-OHB) in RAW246.7 macrophages in vitro. We found that β-OHB inhibits macrophage proliferation. Mechanistically, β-OHB inhibits macrophage proliferation may be via the FFAR3-AKT pathway. Collectively, our study indicated that KD ameliorates UUO-induced renal fibrosis by regulating macrophage proliferation. KD may be an effective therapy method for renal fibrosis due to its protective impact against the disorder.Copyright © 2023 Elsevier Ltd. All rights reserved.