This study aimed to investigate the possible protective effect of paricalcitol on experimental amikacin-induced nephrotoxicity model in rats. Wistar albino rats (n=32) were allocated into four equal groups of eight each, the control (Group C), paricalcitol (Group P), amikacin-induced nephrotoxicity (Group A), and paricalcitol-treated amikacin-induced nephrotoxicity (Group A+P) groups. Paricalcitol was given intra-peritoneally at a dose of 0.4g/kg/d for 5 consecutive days prior to induction of amikacin-induced nephrotoxicity. Intra-peritoneal amikacin (1.2g/kg) was used to induce nephrotoxicity at day 4. Renal function parameters, oxidative stress biomarkers, oxidative DNA damage (8-hydroxy-2-deoxyguanosine/deoxyguanosine ratio), kidney histology, and vascular endothelial growth factor (VEGF) immunoexpression were determined. Group A+P had lower mean fractional sodium excretion (p<0.001) as well as higher creatinine clearance (p=0.026) than the amikacin group (Group A). Renal tissue malondialdehyde levels (p=0.035) and serum 8-hydroxy-2-deoxyguanosine/deoxyguanosine ratio (8-OHdG/dG ratio) (p<0.001) were significantly lower; superoxide dismutase (p=0.024) and glutathione peroxidase (p=0.007) activities of renal tissue were significantly higher in group A+P than in group A. The mean scores of tubular necrosis (p=0.024), proteinaceous casts (p=0.038), medullary congestion (p=0.035), and VEGF immunoexpression (p=0.018) were also lower in group A+P when compared with group A. This study demonstrates the protective effect of paricalcitol in the prevention of amikacin-induced nephrotoxicity in an experimental model. Furthermore, it is the first study to demonstrate that paricalcitol improves oxidative DNA damage in an experimental acute kidney injury model.