Background: Chronic inflammation and immune dysregulation are key drivers of diabetes complications. Rivaroxaban (RX) and sitagliptin (SITA) are established therapies for thromboembolism and glycemic control, respectively. This study evaluated the novel therapeutic potential of nano-rivaroxaban (NRX) alone and in combination with sitagliptin (SITA) in mitigating inflammation and restoring immune balance in streptozotocin (STZ)-induced diabetic rats. Methods: Type 2 diabetes was induced in rats using a single injection of STZ (60 mg/kg). Animals were divided into five groups: control, STZ-diabetic, RX-treated (5 mg/kg), NRX-treated (5 mg/kg), and NRX+SITA-treated (5 mg/kg + 10 mg/kg). After 4 weeks of treatment, blood glucose, coagulation markers, pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and anti-inflammatory cytokines (IL-35, TGF-β1, IL-10) were analyzed. Histopathological examination of the liver, kidney, pancreas, and spleen was conducted. Immunohistochemistry was used to assess hepatic NF-κB expression. Results: STZ significantly elevated pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and anti-inflammatory cytokines (IL-35, TGF-β1, IL-10), along with increased hepatic NF-κB expression and histopathological abnormalities in immune organs. NRX significantly reduced inflammatory cytokines, improved histopathological changes in organs, and decreased hepatic NF-κB expression. The combination therapy (NRX + SITA) achieved superior immune modulation, with enhanced cytokine profile restoration, reduced hepatic NF-κB expression, and near-complete histopathological normalization. Conclusions: This study underscores the promise of combining nanoparticle-based drug delivery with established therapies like sitagliptin to achieve superior immune modulation and inflammation control, presenting a potential therapeutic strategy for managing diabetes complications.