Target identification is crucial for elucidating the mechanisms of bioactive molecules in drug discovery. However, traditional methods assess compounds individually, making it challenging to efficiently examine multiple compounds in parallel, especially for structurally diverse compounds. This study reports a novel strategy called chemical genomics-facilitated chemical proteomics (CGCP) for multiplexing the target identification of bioactive small molecules. CGCP correlates compounds' perturbation of global transcription, or chemical genomic profiles, with their reactivity toward target proteins, enabling simultaneous identification of targets. We demonstrated the utility of CGCP by studying the targets of celastrol (Cel) and four other electrophilic compounds with varying levels of similarity to Cel based on their chemical genomic profiles. We identified multiple novel targets and binding sites shared by the compounds in a single experiment. CGCP enabled multiplexity and improved the efficiency of target identification for structurally distinct compounds, indicating its potential to accelerate drug discovery.