β-Hydroxybutyrate (β-HB), the primary circulating ketone body, plays a dual role as both a metabolic fuel and an endogenous signaling molecule, offering diverse systemic benefits. Recent studies have highlighted the renoprotective effects of exogenous β-HB therapy in various animal models of kidney disease. In this investigation, our goal was to assess whether pre-treatment with exogenous β-HB could alleviate kidney damage in a mouse model of cisplatin-induced acute kidney injury (AKI). Prior to cisplatin administration, intraperitoneal administration of β-HB was carried out, and the groups were classified into four: Sham, β-HB, cisplatin, and β-HB + cisplatin. The tubular damage score and serum creatinine levels were significantly lower in the β-HB + cisplatin group compared to the cisplatin group. Furthermore, the expression of phosphorylated NF-κB, inflammatory cytokines, and the quantity of F4/80-positive macrophages in the β-HB + cisplatin group were reduced compared to those in the cisplatin group. Additionally, oxidative stress markers for DNA, protein, and lipid in the β-HB + cisplatin group were markedly diminished compared to those in the cisplatin group. The number of TUNEL-positive and cleaved caspase 3-positive tubular cells in the β-HB + cisplatin group was lower than in the cisplatin group. Pre-treating with exogenous β-HB effectively mitigated kidney damage by suppressing inflammation, oxidative stress, and tubular apoptosis in cisplatin-induced AKI. Therefore, exogenous β-HB as a pre-treatment emerges as a promising and novel strategy for preventing cisplatin-induced AKI.