This study develops a coupled waveguide-surface plasmon resonance (CWSPR) biosensor with a sub-wavelength grating structure for the real-time analysis of biomolecular interactions. In the proposed optical metrology system, normally incident white light is coupled into the waveguide layer through the sub-wavelength grating structure thereby enhancing the wave vector which excites the surface plasmons on the metal sensing surface. The proposed CWSPR biosensor not only retains the same sensing sensitivity as that of a conventional surface plasmon resonance device, but also yields a sharper dip in the reflectivity spectrum and therefore provides an improved measurement precision. Moreover, the metrology setup overcomes the limitations of the conventional Kretschmann attenuated total reflection approach and is less sensitive to slight variations in the angle of the incident light. The experimental results confirm that the current CWSPR biosensor provides a straightforward yet powerful technique for real-time biomolecular interaction analysis.