Ongoing advances in CuII-catalyzed aerobic oxidative coupling reactions between arylboronic esters and diverse heteroatom nucleophiles have strengthened the development of the general Chan-Lam (CL) based reaction protocol, including the C−O bond formation methodologies. In-depth mechanistic understanding of CL etherification with specific emphasize on different reaction routes and its energetics are still lacking, even though the reaction has been experimentally explored. Here, we present a DFT-guided computational study to unravel the mechanistic pathways of the CL-based etherification reaction. The computational findings provide some interesting insights on the fundamental steps of the catalytic cycle, particularly the rate-determining transmetalation event. Aryl boronic ester coordinated, methoxide bridged CuII intermediate acts as resting state, which undergoes transmetalation accompanying an activation barrier of 20.4 kcal/mol. The energy spans of the remaining fundamental steps leading to the methoxylated product are relatively low. The minor product requires an additional 14.2 kcal/mol energy span to surmount in comparison to the favored route. Hammett studies for the substituted aryl boronic esters reveal higher reaction turnover for electron-rich aryl systems. The results agree with the previously reported spectroscopic and kinetic observations. For a series of alcohol substrates, it was observed that except for cyclohexanol, moderate to high etherification turnovers are predicted.