Objective: To evaluate the protective effect of the coconut oil nanoemulsion against methotrexate-induced hepatotoxicity and nephrotoxicity in Ehrlich ascites carcinoma-bearing Swiss albino mice. Methods: Forty mice were divided into four groups. Group Ⅰ served as the untreated Ehrlich ascites carcinoma-bearing mice while Ehrlich ascites carcinoma-bearing mice in groups Ⅱ–Ⅳ received an intraperitoneal injection of 0.2 mL/kg coconut oil nanoemulsion, 20 mg/kg methotrexate as well as 0.2 mL/kg coconut oil nanoemulsion mixed with 20 mg/kg methotrexate, respectively. The toxicities of the treatments were assessed by determining the complete blood count, performing the serum analysis for liver and kidney functions, evaluating the oxidative status and visualizing histological changes in the liver and kidney tissues. Results: Treatment with methotrexate and coconut oil nanoemulsion markedly diminished the liver parameters including aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total protein, direct bilirubin and total bilirubin which were raised by methotrexate treatment (P < 0.05). Similarly, creatinine and blood urea nitrogen, as the indicators of kidney function, were dramatically lowered in the combination treatment group compared to the methotrexate group (P < 0.05). In addition, treatment with methotrexate and coconut oil nanoemulsion reduced the malondialdehyde and increased catalase, glutathione reductase and superoxide dismutase, in the liver and kidney tissues (P < 0.05). The treatment with methotrexate and coconut oil nanoemulsion reduced white blood cell count and increased the hemoglobin amount (P < 0.05), but did not cause any change in platelets and red blood cell count. Conclusions: Coconut oil nanoemulsion as a nanocarrier has great potential in reducing the adverse side effects induced by methotrexate.