In order to monitor analytes in liquid matrices, optical fiber probes in reflection mode can be exploited in several application fields. This work presents a novel sensing approach based on C-shaped waveguides obtained by filling PVC C-shaped channels with microbeads of molecularly imprinted polymers (MIP-microbeads). Specifically, for the first time, MIP microbeads are used as a sensitive core of optical waveguides with several advantages. The MIP microbeads C-shaped waveguide is in contact with a polished plastic optical fiber (POF) at one end to connect the sensitive region with the light source and the detector in a reflection-based scheme via a simple POF-based splitter. As a proof of concept, the MIP-microbeads were prepared using 2-furaldehyde (2-FAL) as the template to compare the results with other optical fiber sensors. Moreover, to highlight the performance improvement of the proposed sensing approach compared to MIP-based configurations, a sensor based on an MIP (MIP-mass sensor) instead of MIP-microbeads has been developed, tested, and compared with the MIP-microbeads sensor and the state-of-the-art. The results obtained via the MIP-microbeads sensor demonstrated the best performance, with an ultra-low detection limit at a pico-nano molar level and an ultra-wide detection concentration range of about four orders of magnitude. Moreover, the proposed optical-chemical sensor probe is small-size (at a micron scale), simple to realize, low-cost, mechanically robust, suitable for installation even in extreme conditions, and can be used in a real scenario where a reflection scheme sensor is required. An experimental test in the food application field is reported.