The lychee is a fruit widely appreciated and stands out as a functional food. However few studies have focused on its residues, such as seeds and skins that are usually treated as residue by the industrial sector. Thus the aim of this study was to evaluate the conditions of extraction of phenolic compounds from the lychee residues with ethanolic solutions by response surface methodology and evaluate antioxidant activity. The concentration of phenolic compounds and antioxidant activity in the skin, pulp, and seeds of the fruit was determined. To optimize the extraction process, independent variables (ethanol concentration and temperature) and dependent (total phenolic) were studied. The samples of lychee were separated in pulp, seed and skin and were dried in oven at 40°C. The extracts were produced always in the ratio 1:30 (w/v) of sample and solvent by 50 minutes in a water bath at 200 rpm. The amount of total phenolic was measured by Folin Ciocalteau and expressed as mg of gallic acid per gram of dry fruit. The antioxidant activity was measured by DPPH, expressed as trolox equivalents. It was observed that the skin showed the higher results to total phenolic and antioxidant activity followed by seed and pulp, and because of that, the skin was chosen to optimize the extraction conditions. The optimal concentration of ethanol for the extraction of phenolic to skin of lychee was around ethanol 50% (v/v) and the temperature around 45°C, the best result obtained of total phenolic compounds in the experimental design was 25.87 (mgGAE/g). The antioxidant activity was 43.09 µmol of trolox/g, higher of some food considered sources of antioxidants. The extraction of phenolic compounds of skin of lychee was optimized and showed considerable antioxidant activity, proving to be an important source of these compounds in a residue not used by industry.