Background: Renal and cardiovascular complications stand as the primary contributors to both mortality and morbidity among individuals with diabetes. Polydatin (Pd) has garnered attention for its potential roles as an anti-inflammatory, anti-oxidant, and protector of the kidneys and heart. Nanoparticles are being developed to aid in the early diagnosis of diabetes through imaging contrast agents. The aim of this research was to explore the defensive properties of Pd and Polydatin-Chitosan nanoparticles (Pd-NPs) in mitigating diabetic renal-cardiac complications, modulation of oxidative stress and inflammation plays a crucial role. The rats were segregated into four groups: normal, diabetic, diabetic + Pd (diabetic rats treated with 50 mg/kg b. wt of Pd), and diabetic + Pd-NPs (diabetic rats treated with Pd-NPs at a dose of 50 mg/kg b. wt). These treatments were administered orally on a daily basis for a duration of four weeks. Results: Diabetic rats treated with Pd or Pd-NPs resulted in a noteworthy enhancement in renal markers such as creatinine and urea, as well as improvements in heart function indicators by reducing serum levels of creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and troponin I activities when compared to the diabetic control group. The treatment agents not only inhibited the elevated levels of malonaldehyde (MDA) and nitric oxide (NO) but also increased the levels of glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities in the diabetic-treated rats. Additionally, both Pd and Pd-NPs reduced the concentrations of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-18 (IL-18), interleukin-23 (IL-23), atrial natriuretic peptide (ANP), tumor necrosis factor-alpha (TNF-α), and nuclear factor-kappa β (NF-kβ), while elevating the levels of interleukin-10 (IL-10) and interleukin-35 (IL-35). Conclusions: The novel Pd-NPs formulation demonstrated greater efficacy than Pd in ameliorating diabetic cardiomyopathy and nephropathy by their anti-inflammation and anti-oxidant activities.