The detection for small molecules with low concentrations is known to be challenging for current chemical and biological sensors. In this work, we designed a highly sensitive plasmonic biosensor based on the symmetric metal cladding plasmonic waveguide (SMCW) structure for the detection of biomolecules. By precisely designing the configuration and tuning the thickness of the guiding layer, ultra-high order modes can be excited, which generates a steep phase change and a large position shift from the Goos–Hänchen effect (with respect to refractive index changes). This position shift is related to the sharpness of the optical phase change from the reflected signal of the SPR sensing substrate and can be directly measured by a position sensor. Based on our knowledge, this is the first experimental study done using this configuration. Experimental results showed a lateral position signal change > 90 µm for glycerol with a sensitivity figure-of-merit of 2.33 × 104 µm/RIU and more than 15 µm for 10−4 M biotin, which is a low molecular weight biomolecule (less than 400 Da) and difficult to be detected with traditional SPR sensing techniques. Through integrating the waveguide with a guiding layer, a strong improvement in the electric field, as well as sensitivity have been achieved. The lateral position shift has been further improved from 14.17 µm to 284 µm compared with conventional SPR substrate with 50 nm gold on single side. The as-reported sensing technique allows for the detection of ultra-small biological molecules and will play an important role in biomedical and clinical diagnostics.