Oral medication is the most acceptable therapy to treat chronic diseases. Natural drugs and excipients have unique advantages, such as low cost and high safety. We first investigated modified ethanol nanosomes for tumor treatment via oral administration. We loaded curcumin (CM) into small ethanol nanosomes coated with the natural alkaline polysaccharide chitosan (CCSET) for increased absorption and bioavailability and enhanced efficacy against small cell lung cancer (SCLC). Compared to CM and noncoated ethanol nanosomes, CCSETs exhibited superior physicochemical, in vitro/in vivo kinetic, absorptive properties and treatment efficacy at the cellular and animal levels. The interaction of CM and serum albumin (the quantitative binding force) was analyzed. The bioavailability of CCSET increased by 11.84-fold, and the tumor growth inhibition rate increased markedly compared to CM. We first confirmed the effect of CM on SCLC stem cells, and CCSET greatly enhanced this action. We first reported that CM had an antitumor effect on SCLC at the animal level and that CCSET enhanced this effect. Natural alkaline polysaccharide-coated small ethanol nanosomes delivering natural medicine may be a potential oral anticancer strategy.