Response surface methodology (RSM) was used to optimise alkaline protein extraction from cañihua grain meal as to maximise protein extraction yield. Different factors (temperature, extraction time, solvent/meal ratio, pH and NaCl molar concentration) were screened, and their significant influence on the extracted protein yield was evaluated. The first four factors were selected and studied by RSM using a central composite design (CCD). The obtained model produced a satisfactory fitting of the results (R2 = 0.801). Optimal cañihua protein extraction conditions corresponded to a temperature of 21 °C, time extraction of 5 min, solvent/meal ratio of 37/1 (v/w) at pH 10 resulting in a protein yield of 80.4 ± 1.3%, which closely agree with the predicted value of 81.4%. Moreover, protein degradation was studied via differential scanning calorimetry (DSC) obtaining a denaturation temperature of 93.4 °C and an enthalpy value of 1.22 ± 0.05 J g−1. These results are interesting from a technological point to help in designing an optimal protein extraction process and cañihua food processing strategies.