Microfluidic extraction and separation have demonstrated enormous potential in the field of purification and separation, but the essence of its enhanced separation has always been a focus of debate in the academic community. This study reveals that the interaction between extractant molecules and ions in the process of microfluidic extraction exhibits some significant differences from conventional liquid–liquid two phase stirring dispersed droplet extraction. The interaction between extractant molecules and metal ions through the hydrogen bonds (H-bonds) bridged by water molecules around the hydration shell of metal ions exhibits a noticeable change in confined flow in microchannel. It was demonstrated that in our experiments that the strength difference of this interaction is subjected to the ability of different metal ions to bind water molecules. Therefore, the differences in the interaction between extractant molecules and ions through the hydrogen bonding “water-bridge” are easier to be distinguished within the confined fluid, due to the different effects from the confined environment on mass transfer of metal ions with different abilities to bind water molecules. The confined fluid environment strengthened the difference in the interaction, leading to an amplification of difference in ion diffusion rates, thereby achieving enhanced separation of target rare earth Er3+ ions from the coexisting background ions. Hydrophilic coexisting background ions can be separated by reducing the microchannel width, so that the βEr/Al increases from 2.95 to 49.78. However, the relatively hydrophobic background ions can be separated by increasing flow rates, so that the βEr/Mg increases from 75.32 to 299.06. This work provides a new insight into the essence of microfluidic enhanced separation from the perspective of confined H-bonds.