Microdroplet chemistry is emerging as a great tool for accelerating reactions by several orders of magnitude. Several unique properties such as extreme pHs, interfacial electric fields (IEFs), and partial solvation have been reported to be responsible for the acceleration; however, which factor plays the key role remains elusive. Here, we performed quantum chemical calculations to explore the underlying mechanisms of an aza-Michael addition reaction between methylamine and acrylamide. We showed that the acceleration in methanol microdroplets results from the cumulative effects of several factors. The acidic surface of the microdroplet plays a dominating role, leading to a decrease of ∼9 kcal/mol in the activation barrier. We speculated that the dissociation of both methanol and trace water contributes to the surface acidity. An IEF of 0.1 V/Å can further decrease the barrier by ∼2 kcal/mol. Partial solvation has a negligible effect on lowering the activation barrier in microdroplets but can increase the collision frequency between reactants. With acidity revealed to be the major accelerating factor for methanol droplets, reactions on water microdroplets should have even higher rates because water is more acidic. Both theoretically and experimentally, we confirmed that water microdroplets significantly accelerate the aza-Michael reaction, achieving an acceleration factor that exceeds 107. This work elucidates the multifactorial influences on the microdroplet acceleration mechanism, and with such detailed mechanistic investigations, we anticipate that microdroplet chemistry will be an avenue rich in opportunities in the realm of green synthesis.