Sepsis-induced acute kidney injury (SI-AKI) is the most common organ dysfunction of sepsis, characterized with prolonged hospitalization periods and significantly elevated mortality rates. Piplartine (PLG), an alkaloid extracted from Piper longum within the Piperaceae family, has exhibited diverse pharmacological activities, including anti-inflammatory, anti-atherosclerotic, and anti-tumor effects. Herein, we investigated whether the PLG could reverse SI-AKI and explore its possible anti-inflammatory mechanisms. We constructed an SI-AKI model using cecal ligation and puncture (CLP) and systematically evaluated the protective effect of PLG administered by gavage in the SI-AKI mice. Subsequently, we performed proteomic sequencing of the kidney and integrated data from the GeneCards and SwissTargetPrediction databases to identify potential targets and mechanisms. Immunofluorescence and western blotting were used to examine the expression of relevant targets and pathways in vivo and in vitro. The influence of PLG on the predicted target and pathway was verified using an agonist of the target protein and a series of biochemical experiments. PLG exhibited significant efficacy against pathological damage, neutrophil and macrophage infiltration, and macrophage pyroptosis in kidneys at 30 mg/kg. An integrated analysis of proteomic data identified the translocator protein (TSPO) as a potential target for the renoprotective effects of PLG. Moreover, a TSPO agonist (RO5-4864) prominently reversed the protective effect of PLG in SI-AKI mice, as manifested by a deterioration in renal function, histopathological lesions and macrophage pyroptosis in the kidneys. Our results suggest that PLG may ameliorate SI-AKI, potentially through partial inhibition of the TSPO-macrophage pyroptosis pathway.