Detecting specific target analytes and differentiating them from interfering background effects is a crucial but challenging task in complex multi-component solutions commonly encountered in environmental, chemical, biological, and medical sensing applications. Here we present a simple nanoplasmonic interferometric sensor platform that can differentiate the adsorption of a thin protein layer on the sensor surface (surface effects) from bulk refractive index changes (interfering background effects) at a single sensing spot, exploiting the different penetration depths of multiple propagating surface plasmon polaritons excited in the ring–hole nanoplasmonic sensors. A monolayer of bovine serum albumin (BSA) molecules with an effective thickness of 1.91 nm is detected and differentiated from a 10⁻³ change in refractive index unit for the bulk solution. The noise level of the retrieved real-time sensor output compares favorably with that of traditional prism-based surface plasmon resonance sensors, but is achieved using a significantly simpler collinear transmission geometry and a miniaturized sensor footprint.