Histone acetylation, governed by histone deacetylase (HDAC) enzymes, plays a pivotal role in cell biology. Elevated HDAC expression is linked to poor prognosis in various diseases, including cancer, making HDAC inhibitors clinically valuable. Among the 11 metal-dependent HDAC isoforms, the exceptional ability of HDAC11 to regulate both deacetylation and defattyacylation of proteins suggests an expansive role in cellular processes. However, since HDAC11 is one of the least studied HDAC isoforms, the known roles for HDAC11 in cell biology are limited. In this study, proteomics-based mutant trapping was performed to identify non-histone substrates of HDAC11 and link HDAC11 activity to specific cellular events. Proteomics analysis revealed 64 putative substrates, with follow-up studies documenting that HDAC11 deacetylates the BRAF kinase on K680 to suppress kinase activity and cell proliferation. Given the established role of BRAF in cancer, the data suggest that HDAC11-mediated deacetylation influences signaling pathways in tumor progression, underscoring the diverse regulatory role for HDAC11 in cellular events.