Here, we report on systematic investigation of the impact of coextraction of the aqueous electrolyte and anion interference on the response of cation-selective bulk optodes. It is evident that to deliberately manage the properties of chemical sensors and to apply them in routine analysis, one should have exhaustive insight into their operation mechanism. Despite the extensive research in the field of ionophore-based optodes and numerous attempts for their practical application, the understanding of how coextraction of an aqueous electrolyte influences its response characteristics has not been developed thus far. Meanwhile, the electrolyte coextraction determines the detection limits of analogous ion-selective electrodes. A theoretical model based on phase distribution equilibrium is proposed to quantitatively describe the effect of Donnan exclusion failure on the response of polymeric plasticized optodes. The theoretical conclusions are confirmed by the results obtained with Na+/pH-selective optodes based on a neutral chromoionophore as a model system in solutions containing anions of various lipophilicities (Cl–, NO3–, I–, SCN–, and ClO4–). For the first time, it is shown that coextraction leads to a significant shift of the response range of the optodes as well as to nonmonotonic response curves due to the transition from cationic to anionic response. An approach to estimate the coextraction constants of electrolytes from the optode response curves is proposed. The limitations in the applicability of optodes due to co-ion interference are explored. It is found that neglecting anion interference can cause dramatic errors in the results of analyses with optical sensors.