Background: Oral malignancies have a significant effect on the quality of life among the affected patients. Curcumin is an antioxidant with a low bioavailability in the target tissue. Niosomes are carriers of increasing the therapeutic effects of drugs and reducing their side effects. This study aimed to determine the effective dose of curcumin niosome in the culture and then to compare its prophylactic effect in the form of mouthwash with that of its injectable form on oral cancer in rats. Methods: This was an in-vitro and in-vivo study. Firstly, KB oral cancer cells and human umbilical vein endothelial cells (HUVEC) were treated in separate groups with free curcumin, curcumin-loaded niosomes, and the unloaded niosomes at four doses of 4, 8, 16, and 32 μg. The study rats were then divided into the following four groups: 1) no intervention, 2) only carcinogenic substance, 3) carcinogenic substance with curcumin-loaded niosome injection, and 4) carcinogenic substance with a mouthwash containing niosome. Results: At the cellular level, a dose of 16 μg after 24 h was selected as an effective dose. In the animal phase, the use of injectable curcumin niosome was observed to significantly prevent the development of severe forms of dysplasia. Conclusions: In this in-vitro and in-vivo study, curcumin-loaded niosome was effective in preventing the development of severe forms of dysplasia and the inhibition of the growth of cancer cells.