Cancer-causing aberrations recurrently target the chromatic-regulatory factors, leading to epigenetic dysregulation. Almost all patients with synovial sarcoma (SS) carry a characteristic gene fusion, SS18::SSX, which produces a disease-specific oncoprotein that is incorporated into the switch/sucrose non-fermentable (SWI/SNF) chromatin-remodeling complexes and profoundly alters their functionalities. Targeting epigenetic dependency in cancers holds promise for improving current treatment. Leveraging on cancer cell dependency dataset, pharmacological tools, and genomic profiling, we find WDR5, a factor critical for depositing histone H3 lysine 4 (H3K4) methylation, to be an unexplored vulnerability in SS. Mechanistically, WDR5 and SS18::SSX interact and colocalize at oncogenes where WDR5 promotes H3K4 methylation and the chromatin association of SS18::SSX-containing chromatin-remodeling complexes. WDR5 degradation by proteolysis-targeting chimera (PROTAC) not only suppresses the SS18::SSX-related oncogenic programs but additionally causes the ribosomal protein deregulations leading to p53 activation. WDR5-targeted PROTAC suppresses SS growth in vitro and in vivo, providing a promising strategy for the SS treatment.