Mounting evidence from clinical and epidemiological studies suggests that lycopene, the most abundant carotenoid in tomatoes, may be beneficial in the prevention or treatment of some important diseases. Ripe tomato peels are the richest source of lycopene, but the use of conventional solvent extraction methods without pretreatment of the plant material results in very poor recovery. The reason lies in the localization of lycopene in the plant tissue and the low permeability of the latter to solvent molecules. In this paper, a mixture design procedure was used to formulate solvent mixtures allowing the recovery of lycopene from non-pretreated tomato peels. Two ternary systems were investigated: (a) n-hexane–ethanol–acetone and (b) ethyl lactate–ethanol–acetone. Optimization of the ternary mixture composition led to a recovery of over 90% of the lycopene present in the peels. The high extraction efficiency was explained in terms of lycopene affinity combined with the ability to swell the plant material. A tomato oleoresin with high antioxidant activity and a lycopene content of about 13% (w/w) was also produced. Overall, the results indicate that highly effective solvents for direct recovery of lycopene from tomato peels can be easily prepared by a mixture design approach.