Alzheimer's disease (AD) is a progressive neurodegenerative disease with insidious onset, and the deposition of amyloid-β (Aβ) is believed to be one of the main cause. Fluorescence imaging is a promising technique for this task, but the Aβ gold standard probe ThT developed based on this still has shortcomings. The development of a new fluorescent probe to detect Aβ plaques is thought to be essential. Herein, a series of red to near-infrared emitting fluorescent probes QNO-ADs with newly quinoxalinone skeleton are designed to detect Aβ plaques. They all demonstrate excellent optical properties and high binding affinity (∼Kd = 20 nM) to Aβ aggregates. As the most outstanding candidate, QNO-AD-3 shows significant signal-to-noise (S/N) ratio at the level of in vitro binding studies, and the brilliant fluorescence staining results in favor of grasping the approximate distribution of Aβ plaques in the brain slice. In vivo Aβ plaques imaging suggests that QNO-AD-3 can cross the BBB and have a long retention time in the brain with low biological toxicity. In addition, the results of docking theoretical calculation also provide some references for the design of Aβ probe. Overall, given the high affinity of QNO-AD-3 and the ability to monitor Aβ plaques for a long time that is not common now, we believe QNO-AD-3 will be an effective tool for an Aβ-related matrix and AD disease research in the future.