A biosensing method combining whispering gallery modes (WGM) with gold nanoparticle (Au NP) assays is presented for label-free protein detection. The method uses high-Q optical resonances to detect protein binding to Au NPs through frequency shifts. A computational model based on generalized Mie theory explains the enhanced sensitivity due to plasmon effects. Bovine serum albumin (BSA) was adsorbed onto Au NPs in a phosphate buffered saline (PBS) solution, then immobilized on an anodic aluminum oxide (AAO) membrane. High-Q WGM resonance frequency shifts were measured after evanescent coupling of a microsphere cavity to the NP layer. The results were fitted to an adsorption isotherm, agreeing with a two-component model. The method achieved picomolar sensitivity, decoupling WGM transducers from NP recognition elements. The Au NP solution with BSA was prepared and captured on the AAO membrane using vacuum suction. The resonant microsphere cavity structure and its orientation with respect to the Au NPs on the AAO membrane are illustrated. A well-established WGM setup monitored real-time WGM resonances of a tapered-fiber-coupled microsphere. Wavelength shifts associated with coupling to NPs were determined by recording and subtracting WGM resonance wavelengths in air and in contact with the NP layer. The silica microsphere probes the NP layer via its evanescent field, extending about 50 nm at 633 nm wavelength. The limited extent of the evanescent field ensures probing only the first layer of Au NPs. The Q factors before coupling the microsphere to Au NPs were ~3×10^6 at 633 nm and ~5×10^6 at 1060 nm. The Au NP WGM shift at ~633 nm was compared to that at ~1060 nm to test for signal enhancement due to plasmon coupling. The shift was larger at ~633 nm, indicating signal enhancement. Numerical calculations based on generalized multi-particle Mie theory revealed detailed WGM interaction with localized surface plasmon (LSP) resonance of Au NPs. The spatial distributions of local field intensity near the microsphere surface at resonance wavelength λ~632 nm in the presence and absence of Au NPs are shown. The fractional wavelength shift of the mode caused by a small protein molecule is proportional to the field intensity and inversely proportional to the energy density integrated over the whole mode volume. The calculations showed that adsorption of a single BSA molecule at the center of the evanescent field does not produce a detectable shift, but placing BSA in the hot spot of the WGM-coupled NP causes a detectable shift. The hybrid WGM-NP sensor has higher sensitivity due to the larger Q-factors of hybrid photonic-plasmonic modes. The method wasA biosensing method combining whispering gallery modes (WGM) with gold nanoparticle (Au NP) assays is presented for label-free protein detection. The method uses high-Q optical resonances to detect protein binding to Au NPs through frequency shifts. A computational model based on generalized Mie theory explains the enhanced sensitivity due to plasmon effects. Bovine serum albumin (BSA) was adsorbed onto Au NPs in a phosphate buffered saline (PBS) solution, then immobilized on an anodic aluminum oxide (AAO) membrane. High-Q WGM resonance frequency shifts were measured after evanescent coupling of a microsphere cavity to the NP layer. The results were fitted to an adsorption isotherm, agreeing with a two-component model. The method achieved picomolar sensitivity, decoupling WGM transducers from NP recognition elements. The Au NP solution with BSA was prepared and captured on the AAO membrane using vacuum suction. The resonant microsphere cavity structure and its orientation with respect to the Au NPs on the AAO membrane are illustrated. A well-established WGM setup monitored real-time WGM resonances of a tapered-fiber-coupled microsphere. Wavelength shifts associated with coupling to NPs were determined by recording and subtracting WGM resonance wavelengths in air and in contact with the NP layer. The silica microsphere probes the NP layer via its evanescent field, extending about 50 nm at 633 nm wavelength. The limited extent of the evanescent field ensures probing only the first layer of Au NPs. The Q factors before coupling the microsphere to Au NPs were ~3×10^6 at 633 nm and ~5×10^6 at 1060 nm. The Au NP WGM shift at ~633 nm was compared to that at ~1060 nm to test for signal enhancement due to plasmon coupling. The shift was larger at ~633 nm, indicating signal enhancement. Numerical calculations based on generalized multi-particle Mie theory revealed detailed WGM interaction with localized surface plasmon (LSP) resonance of Au NPs. The spatial distributions of local field intensity near the microsphere surface at resonance wavelength λ~632 nm in the presence and absence of Au NPs are shown. The fractional wavelength shift of the mode caused by a small protein molecule is proportional to the field intensity and inversely proportional to the energy density integrated over the whole mode volume. The calculations showed that adsorption of a single BSA molecule at the center of the evanescent field does not produce a detectable shift, but placing BSA in the hot spot of the WGM-coupled NP causes a detectable shift. The hybrid WGM-NP sensor has higher sensitivity due to the larger Q-factors of hybrid photonic-plasmonic modes. The method was