Ni-catalyzed selective C-O bond activation opens a door for the cross-coupling of aryl esters. The present study reports a thorough theoretical analysis of Ni-catalyzed cross-coupling between aryl esters and arylboronic acids, with an emphasis on explaining the cause for the surprising selectivity in C-O activation. The overall catalytic cycle is found to include three basic steps: oxidative addition, transmetalation, and reductive elimination. Oxidative addition of Ar-OAc to Ni(0) in the presence of PCy3 ligand proceeds through the monophosphine pathway (instead of the alternative two-phosphine pathway) with a relatively low barrier of +22.9 kcal/mol. Transmetalation proceeds via a base-assisted mechanism with a barrier of +31.2 kcal/mol. Reductive elimination is the most facile step in the whole catalytic cycle. Comparatively, oxidative addition of ArO-Ac to Ni(0) is a more facile process (barrier = +14.2 kcal/mol) than oxidative addition of Ar-OAc to Ni(0). However, the former process is associated with a fairly low reverse barrier, and its product does not transmetalate easily (barrier = +33.1 kcal/mol). By comparison, the latter process is an irreversible reaction, and its product transmetalates more readily. These results explain why only the cross-coupling products from the Ar-OAc activation (but not from the ArO-Ac activation) were observed in experiments.