This work reports the development and application of two liquid-core microstructured polymer optical fibers (LCmPOF) with different microstructure sizes. They are used in a fiber-enhanced Raman spectroscopy sensing platform,with the aim of detecting glucose in aqueous solutions in the clinically relevant range for sodium–glucose cotransporter 2 inhibitor therapy. The sensing platform is tested for low-concentration glucose solutions using each LC-mPOF. Results confirm that a significant enhancement of theRaman signal is achieved in comparison to conventional Raman spectroscopy. Additional measurements are carried out to obtain the valid measurement range, the resolution, and the limit of detection, showing that the LC-mPOF with 66-μm-diameter central hollow core has the highest potential for future clinical applications. Finally, preliminary tests successfully demonstrate glucose identification in urine.