Cereblon (CRBN)-based protein degradation, via molecular glue degraders (MGDs) and proteolysis-targeting chimeras (PROTACs), is a promising cancer treatment strategy in targeted protein degradation (TPD). However, novel degraders discovery remains limited due to the lack of robust, high-throughput screening (HTS) methods for processing pools of purified compounds or complex chemical synthesis mixtures. Here, we introduce an innovative HTS strategy that employs a highly sensitive, fluorescence-coupled ubiquitination assay to identify CRBN-based degraders. This approach tracks ubiquitinated target proteins via gel-based analyses, and thereby progressively narrows down the list of potential degrader molecules from large-scale compound libraries or chemical reaction mixtures. Using this strategy, we identified LL-BPTF-8, a promising lead compound of PROTAC degrader with high potency and selectivity that targets the bromodomain PHD finger transcription factor (BPTF). Overall, our method offers a low-cost, rapid, and versatile platform for the HTS of protein degrader candidates, significantly streamlining the discovery of novel degraders.