The present work demonstrates the integration of hollow core photonic crystal fibers (HC-PCF), microfluidics, and statistical analysis for monitoring biomolecules using Raman spectroscopy. HC-PCF as a signal enhancer has been proven by many researchers. However, there have been challenges in using HC-PCF for practical applications due to limitations such as coupling, stability, evaporation, clogging, consistent filling, and reusing the same fiber. This limited the potential of HC-PCF to detect low concentrations of liquid samples, which is why HC-PCF still hasn’t transcended the lab barriers. The current device is based on an H-design lay-out which uses the pressure difference between the two ends of the fiber for filling and flushing the liquid samples. This mitigated several issues related to device performance by allowing us to fill the fiber with liquid samples consistently, rapidly and reproducibly. The resulting Raman signals were significantly more stable as various concentrations of ethanol in water were sequentially introduced into the fiber. The scheme also allowed us to overcome the barrier of predicting low concentrations by applying Partial Least Square (PLS) technique which was done for the first time using HC-PCF. Thus, the present scheme paves path for the inclusion of HC-PCF in the main stream point-of-care technology.