Background <p>Given the elevated mortality rates and significant treatment costs associated with sepsis, characterized by a dysregulated host response to infection and life-threatening organ dysfunction, the search for treatment strategies involving new and potentially effective agents is essential. Sunitinib, a tyrosine kinase inhibitor, shows promise for mitigating increased inflammation in sepsis through its modulation of specific molecular pathways. This study investigates the effects of sunitinib in the treatment of sepsis.</p> Methods <p>Sepsis was induced in rats using the cecal ligation and puncture (CLP) model and sunitinib treatment was administered orally at various dosages. The effects of sunitinib treatment were evaluated through molecular and histopathological methods. The impact of sunitinib treatment on survival was analyzed using Kaplan–Meier survival analysis.</p> Results <p>With low-dose treatment, sunitinib was observed to reduce the levels of proinflammatory cytokines, including interleukin-6, interleukin-8, and TNF-α. However, no reduction was observed with high-dose sunitinib in comparison to the sepsis group. Polymerase chain reaction results indicated that the NLRP3 inflammasome pathway was attenuated with low-dose sunitinib treatment. Furthermore, the extent of sepsis associated histopathological and immunohistochemical changes was reduced with sunitinib treatment, as demonstrated by hematoxylin and eosin staining and immunohistochemical analysis. Survival analysis revealed that the group receiving low-dose sunitinib had the highest survival rate.</p> Conclusion <p>Different sunitinib doses in sepsis treatment yield significantly different molecular results, histopathological outcomes, and survival rates. A comprehensive investigation of tyrosine kinase inhibitor drugs such as sunitinib in the treatment of sepsis will enhance the efficacy of sepsis therapies.</p>