The control of different electron transport pathways by quantum interference (QI) effects offers a unique opportunity for the modulation of electrical properties in molecular electronic devices and materials. In this work, we propose a chemical way to control the intramolecular electron transport pathways by the localization of the highest occupied molecular orbital (HOMO) distribution. The negative charge injection in para-carbazole by deprotonation exhibited a fourfold suppression of single-molecule conductance, while the conductance is almost the same for meta-carbazole before and after deprotonation. The flicker noise analyses and theoretical simulations revealed the localized distribution of HOMO on the para-carbazole center, leading to the appearance of destructive quantum interference (DQI) effect for the control of electron transport pathway. This strategy of reaction-induced orbital localization offers a new strategy for the control of charge transport through molecular devices and materials.