The effect of substituents on the strength of N–X (X = H, F, and Cl) bonds has been investigated using the high-level W2w thermochemical protocol. The substituents have been selected to be representative of the key functional groups that are likely to be of biological, synthetic, or industrial importance for these systems. We interpreted the effects through the calculation of relative N–X bond dissociation energies (BDE) or radical stabilization energies (RSENX). The BDE and RSENX values depend on stabilizing/destabilizing effects in both the reactant molecule and the product radical of the dissociation reactions. To assist us in the analysis of the substituent effects, a number of additional thermochemical quantities have been introduced, including molecule stabilization energies (MSENX). We find that the RSENH values are (a) increased by electron-donating alkyl substituents or the vinyl substituent, (b) increased in imines, and (c) decreased by electron-withdrawing substituents such as CF3 and carbonyl moieties or through protonation. A different picture emerges when considering the RSENF and RSENCl values because of the electronegativities of the halogen atoms. The RSENXs differ from the RSENH values by an amount related to the stabilization of the N-halogenated molecules and given by MSENX. We find that substituents that stabilize/destabilize the radicals also tend to stabilize/destabilize the N-halogenated molecules. As a result, N–F- and N–Cl-containing molecules that include alkyl substituents or correspond to imines are generally associated with RSENF and RSENCl values that are less positive or more negative than the corresponding RSENH. In contrast, N–F- and N–Cl-containing molecules that include electron-withdrawing substituents or are protonated are generally associated with RSENF and RSENCl values that are more positive or less negative than the corresponding RSENH.