Cation exchange (CE) reactions have emerged as a technologically important route, complementary to the colloidal synthesis, to produce nanostructures of different geometries and compositions for a variety of applications. Here it is demonstrated with first-principles simulations that an interstitial impurity cation in CdSe nanocrystals weakens nearby bonds and reduces the CE barrier in the prototypical exchange of Cd2+ ions by Ag+ ions. A Wannier function-based tight binding model is employed to quantify microscopic mechanisms that influence this behavior. To support our model, we also tested our findings in a CE experiment: both CdSe and interstitially Ag-doped CdSe nanocrystals (containing 4% of Ag+ ions per nanocrystal on average) were exposed to Pb2+ ions at room temperature and it was observed that the exchange reaction proceeds further in doped nanocrystals. The findings suggest doping as a possible route to promote CE reactions that hardly undergo exchange otherwise, for example, those in III-V semiconductor nanocrystals.