Sepsis is a life-threatening condition that often results in severe brain injury, primarily due to excessive inflammation and mitochondrial dysfunction. This study aims to investigate the neuroprotective effects of Apelin-13, a bioactive peptide, in a rat model of sepsis-induced brain injury (SBI). Specifically, we examined the role of Apelin-13 in regulating mitophagy through the phosphatase and tensin homolog-induced putative kinase 1 (PINK1)/Parkin pathway and its impact on nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome-mediated pyroptosis and oxidative stress. A sepsis model was induced in male Sprague-Dawley rats ( n = 110, 200-230 g, 12 weeks old) through cecal ligation and puncture (CLP). The septic rats received Apelin-13 (20 μg/kg, intravenously), either alone or combined with mitochondrial division inhibitor-1 (Mdv-1), a mitophagy inhibitor, before undergoing CLP surgery. Survival rates were assessed over a 72-h period, while the cognitive function was evaluated using the Morris water maze over 5 days. Western blotting and immunohistochemistry were utilized to measure the expression levels of NLRP3, cleaved caspase-1, N-terminal fragment of gasdermin D, PINK1, and Parkin in the brains of the rats. In addition, enzyme-linked immunosorbent assays were conducted to evaluate markers of oxidative stress and inflammatory responses in brain samples. Apelin-13 significantly improved survival rates and cognitive function and mitigated brain injury in septic rats. The treatment enhanced PINK1/Parkin-mediated mitophagy and suppressed NLRP3 inflammasome activation, leading to a reduction in pyroptosis, inflammation, and oxidative stress. Inhibition of mitophagy by Mdv-1 significantly reversed the protective effects of Apelin-13 in septic rats. Our findings suggest that Apelin-13 provides neuroprotection in sepsis by modulating mitophagy and inhibiting pyroptosis. These results highlight the potential of Apelin-13 as a therapeutic strategy for SBI.