A series of 2-alkyl- and 2-aryl-1,1,3,3-tetramethylguanidine derivatives were synthesized, and their application in L-Lactide (LA) polymerization was studied. Bn-TMG was the best catalyst in LA polymerization ( [Bn-TMG] = 5 mM, conversion = 94 % after 4 h at 25 °C) compared to other monoguanidine derivatives. In addition, the catalytic activities of C2-dTMG exhibited higher catalytic activity than Bn-TMG, nBu-TMG (monoguanidine derivatives), and C3-dTMG (diguanidine derivative). Density functional theory calculations revealed that Bn-TMG deprotonated benzyl alcohol enhanced benzyl alcohol's initiation ability to LA, and the protonated Bn-TMG activated LA ring-opening process by interacting with the ether oxygen atom of LA. Bn-TMG presented excellent catalytic activity and controllability for LA polymerization at 25 °C.