The rate constants (at 25 °C) for the alkaline hydrolysis of a series of seven acetanilide derivatives were experimentally determined. The series included the parent compound of acetanilide and the following para substituents: CH3, OCH3, NH2, CHO, COCH3, NO2. The obtained kinetic data were then correlated with the following theoretically estimated reactivity indices: Mulliken and NBO atomic charges, the Parr electrophilicity index (...), and the electrostatic potential at the carbon and nitrogen atoms of the reaction center (V_C, V_N). A very good correlation between the logarithm of the rate constant, ln k, and ... values was established. Excellent correlations between V_C and V_N with ln k were found. The data obtained show that the model-independent electrostatic potential at the nuclei (EPN) provides a reliable quantitative approach in describing the reactivity of organic compounds.