CELF6 is a CELF-RNA-binding protein, and thus part of a protein family with roles in human disease; however, its mRNA targets in the brain are largely unknown. Using cross-linking immunoprecipitation and sequencing (CLIP-seq), we define its CNS targets, which are enriched for 3′ UTRs in synaptic protein-coding genes. Using a massively parallel reporter assay framework, we test the consequence of CELF6 expression on target sequences, with and without mutating putative binding motifs. Where CELF6 exerts an effect on sequences, it is largely to decrease RNA abundance, which is reversed by mutating UGU-rich motifs. This is also the case for CELF3–5, with a protein-dependent effect on magnitude. Finally, we demonstrate that targets are derepressed in CELF6-mutant mice, and at least two key CNS proteins, FOS and FGF13, show altered protein expression levels and localization. Our works find, in addition to previously identified roles in splicing, that CELF6 is associated with repression of its CNS targets via the 3′ UTR in vivo. Display omitted •CELF6 primarily associates with 3′ UTRs of synaptic genes in the mouse brain•CELF6:sequence interaction is assayed using a massively parallel reporter assay•CELF3–6 all result in lower mRNA levels with few changes to translation efficiency•CELF6 targets are derepressed in vivo in Celf6-knockout mice Rieger et al. assay the function of the RNA-binding protein CELF6 by defining its targets in the brain. They show that CELF6 largely binds 3′ UTRs of synaptic mRNAs. Using a massively parallel reporter assay, they further show that CELF6 and other CELFs are associated with lower mRNA abundance and that targets are derepressed in Celf6-knockout mice in vivo.