This work presents the development of a novel photonic-based sensor on a nanoscale patterned polydimethylsiloxane (PDMS) substrate acting as transducer, combined with a molecularly imprinted polymer for the rapid and sensitive detection of C-reactive protein (CRP). A silicon wafer was patterned using electron-beam lithography with a one-dimensional (1D) reflective grating (periodicity of about 400 nm) and then replicated using nanoimprint lithography. The latter silicon mould was used for replica moulding to generate a patterned PDMS. The unique 1D design gave PDMS photonic properties that were suitable as a substrate to assemble the biorecognition layer. The surface of the photonic PDMS was modified to become hydrophilic and additionally functionalized with vinyl silane groups to bind the imprinted polymer, resulting in a photonic molecularly imprinted polymer substrate (PMIPS). The developed method was successfully used to detect CRP in serum samples. The reflectance intensity decreased with increasing CRP concentrations, and the sensing PMIPS showed a linear response between 0.005 and 1.215 µg mL−1, a limit of detection of 0.003 µg mL−1, and a selective response to CRP when tested against serum calprotectin. Overall, this novel optical sensor can be used to detect CRP, a serum biomarker of inflammation, particularly in inflammatory bowel diseases.