Several modified celluloses have shown profound benefits in several areas of application. However, there is a lack of little information on the safety profile of most modified celluloses such as cellulose ester. In response to this, cellulose (WMC) was isolated from the watermelon exocarp (WM) of the unexploited watermelon fruit. WMC was converted to cellulose ester (WMS) by simple modification with sebacic acid. WM, WMC and WMS were characterized using X-ray diffraction (XRD), particle size distribution (PSD), Fourier-transform infrared spectroscopy (FTIR), thermogravimetric (TG) analysis, zeta potential and scanning electron microscopy (SEM). The diffractogram revealed that WMS might be classified as cellulose I with a crystallinity of 78.21%. Its surface appears homogeneous, lumpish, having white gel appearance with agglomerates. The impact of WMS on hepato-renal functional indices and hepatic oxidative stress parameters was examined in male Wistar rats for 14 days. At the end of the 14-day exposure, WMS reduced malondialdehyde and nitric oxide concentrations, while glutathione peroxidase activity was significantly elevated, especially at the dose of 200 mg/kg. Also, microscopic analysis of the hepato-renal organs revealed histological abnormalities. Quantum chemical parameters using the density functional theory (DFT) approach were applied to gain theoretical insight into the renotoxic effect exhibited by WMS in molecular terms. The lowest unoccupied molecular orbital (LUMO) and the highest occupied molecular orbital (HOMO) are distributed over the molecules of WMS, suggesting that its renotoxic effect may have occurred via donor–acceptor interactions. Taken together, our data suggest an increase in the susceptibility of kidney to toxicity after subacute exposure to WMS.