Unlocking flexibility on the demand side is a prerequisite for balancing supply and demand in distribution networks with high penetration levels of renewable energy sources that lead to high volatility in energy prices. The main means of fully gaining access to the untapped flexibility is the application of demand response (DR) schemes through aggregation. Notwithstanding, to extract the utmost of this potential, a combination of performance-, financial-, and technical-related parameters should be considered, a balance rarely identified in the state of the art. The contribution of this work lies in the introduction of a holistic DR framework that refines the DR-related strategies of the aggregator towards optimum flexibility dispatch, while facilitating its cooperation with the distribution system operator (DSO). The backbone of the proposed DR framework is a novel constrained-objective optimisation function which minimises the aggregator’s costs through optimal segmentation of customer groups based on fairness and reliability aspects, while maintaining the distribution balance of the grid. The proposed DR framework is evaluated on a modified IEEE 33-Bus radial distribution system where a real DR event is successfully executed. The flexibility of the most fair, reliable and profitable sources, identified by the developed optimisation function, is dispatched in an interoperable and secure manner without interrupting the normal operation of the distribution grid.