Quality by Design (QbD) approach was followed having as analytical target profile the determination of different antimigraine drugs (seven triptans, TRP) available on the market. Multivariate strategies were used for defining the design space and solvent-modified MEKC was the selected analytical method. The versatility of electrophoretic technique, allowing a fine modulation of experimental parameters, made it possible to define the design space (DS). The DS limited a suitable range of experimental parameters in which all possible combinations of variables led to an electrokinetic method able to determine all the considered analytes with a predefined quality. Design of experiments and risk analysis fully assisted the method development from the initial investigation of MEKC knowledge space to the DS definition and finally to the control strategy. Applying the working operative conditions, the baseline separation of TRP was obtained in less than 9 min. The method was finally used for the quantification of three TRP in different pharmaceutical products.