Objective Nagaparpam (NP), a herbo-mineral based Siddha medicine is widely used across the various parts of India for the treatment of various gastric ailments and other kidney related diseases. The lack of scientific evidence regarding the toxicity and efficacy of this drug upon prolonged usage by pyelonephritic patients probed us to initiate this study. Methods The commercially available NP was analyzed for its solubility. The olive oil enriched emulsion was tested for the various phyto-compounds present in the drug. The anti-oxidant profile was evaluated followed by MIC and MBC of the emulsion with incremental concentration drug against Uropathogenic E.coli (UPEC) RRL - 02. Pyelonephritis was induced in experimental mice (n=18) for studying the efficacy and toxicity of NP by trans-urethral catheterization. Upon establishment of infection, the mice were separated into four groups (Group 1: Control, Group 2: Pyelonephritic model, Group 3: Amoxicillin (100 mg/ Kg body weight) and Group 4: NP (600 mg/Kg body)) of six animals each and treated with the NP emulsion for a period of 30 days. Urinary and tissue biochemical components such as protein, SOD, and catalase were monitored regularly and the histological examination were carried out on the formalin fixed kidney samples. Results The NP emulsion contained various phyto-compounds such as tannins, glycosides and saponins. The emulsion had a bacteristatic effect on the pathogenic strain used in the study at 600 mg/Kg body weight, which was used as the concentration for the further in vivo studies. The administration of NP for a period of 10 days had a significant effect in restoring the reduced protein (p< 0.001) levels in the kidney and a decrease in the levels of SOD and catalase was observed relative to the control. However, the prolonged administration of the drug was found to be toxic to the mice at this concentration, which was reflected by the elevated levels of SOD and catalase with a significant decrease in the tissue protein levels (p< 0.01) at the end of the experimental period. This was also evidenced by the damage to the glomerular and tubular regions of the kidney in the NP treated animals. Conclusion NP although effective in treating pyelonephritis at 600 mg/Kg bodyweight, was found to be toxic when administered for prolonged periods of time.