Investigating the binding kinetics of small molecule analytes to larger ligands, such as proteins and antibodies, is a compelling task for the field of drug and biomarker development, as well as the food industry and agro-biotechnology. Here, we improve the limit of detection of the Interferometric Reflectance Imaging Sensor (IRIS), a label-free, highly multiplexed biosensor, to perform real-time affinity measurement of small molecules binding to immobilized antibodies in a microarray format. As the analytes bind to the surface probes, the biomass accumulation on the surface is quantified by measuring the optical reflectance from the layered Si/SiO2 chip through the solution, in a common-path interferometer configuration. As a proof of concept, label-free detection of biotin molecules binding to immobilized streptavidin probes is performed, achieving 1 pg/mm2 sensitivity through signal averaging in a shot noise limited operation. Furthermore, we apply the optimized sensor to the screening of a 20-multiplexed antibody chip (MW~150 kDa ligands) against Fumonisin B1 (MW = 721.8 Da), one of the most prevalent mycotoxins found in many cereal grains such as corn and wheat. The simultaneously recorded binding curves of the toxin to the multiplexed sensor yield a signal-to-noise ratio of ≈8 when noise reduction methods of spatial and temporal averaging are utilized.