This dataset contains proteomic analyses of synaptosomal and cytosolic fractions isolated from the cortex and hippocampus of adult male wild-type (WT) and Chordin-like 1 (Chrdl1) knockout (KO) mice. The study was designed to investigate how loss of Chrdl1 affects the proteomic profile of these two brain regions under physiological conditions, with a particular focus on the synaptic proteome. Isolated fractions were processed and analyzed by liquid chromatography–tandem mass spectrometry (LC-MS/MS).