We report the detailed mechanistic insights of L-proline catalyzed, solvent-controlled, regioselective Mannich reaction. Different solvation models were employed to understand the formation of critical intermediates. The seminal difference in the nature of H-acceptor solvents and H-donor solvents leads to variation in the attachment site on the reactant molecule. Our calculations suggest that the H-acceptor solvent exhibits selective non-covalent interaction with α-hydrogen atoms of the iminium group, facilitating the reactivity at the more hindered site, which results in the formation of a branched isomer. On the other hand, the H-donor solvent preferentially binds to the carboxylate group, thus enabling the reactivity to proceed from the less hindered carbon chain, leading to a linear isomer. The above distinct interactions force a regioselective generation of enamines. Thus, the iminium ion's site-specific solvent interaction has been observed to cause a switch in the regioselectivity. These enamines subsequently react with cyclic ketone to produce Mannich base with excellent enantioselectivity (>99%ee).