This report introduces a local-magnetic-reversal-nucleation based giant magnetoresistance (GMR) sensor with a large sensing area and further discusses its novel sensing scheme of high magnetic moment nanoparticles (MNPs). We demonstrated experimentally that this large-area GMR sensor could successfully detect high moment MNPs. The detection scheme of localized reversal nucleation of GMR sensor induced by MNPs was analyzed and further confirmed by the micromagnetic simulations. This work may provide one pathway in designing next generation GMR biosensors with large area and high sensitivity. This sensing scheme could be applicable to other magnetic biosensors such as magnetic tunnel junction sensors and planar Hall sensors.