DCLK3 (Doublecortin-like kinase 3) is a neuronal kinase enriched in the striatum and in the dentate gyrus of the hippocampus. DCLK3 expression is markedly reduced in the brain of Huntington’s disease (HD) patients. However, its role remains unknown. The laboratory previously showed that DCLK3 could play a neuroprotective role, specifically in different HD models. The overexpression of Dclk3 in the striatum produces neuroprotection against mutant huntingtin (mHtt) toxicity and ameliorates motor deficits in rodent models of HD (knock-in mice with 140 CAG repeats). Our recent results indicate that DCLK3 is localized in the nucleus of neurons and may play a role in transcription through epigenetic mechanisms. Here, we aim at investigating further the role of DCLK3 in the brain. To do so, we generated mice with loxP sites in the Dclk3 gene (DCLK3flox/flox). We first crossed them with CMV-Cre mice to obtain constitutive knockout Dclk3 mice in the whole body. Our behavioral study on memory, anxiety and motor phenotype show no obvious deficit. Likewise, structural analysis in the brain of Dclk3 KO mice in histology and MRI did not highlight any deficit compared to control mice. However the metabolite profile in males at 6 months was slightly but significantly disturbed. Dclk3flox/flox mice were also crossed with Rgs9-cre mice to have Dclk3 deletion in the striatum only. No motor deficits were observed in these mice. Interestingly, the injection of AAV-Cre in the hippocampus of adult Dclk3flox/flox mice tends to produce memory deficits in the water-maze test. These results indicate a potential role of DCLK3 in synaptic plasticity in the hippocampus and suggest that the loss of this protein in HD could contribute to cognitive aspects of the disease. In long term, the signaling involving DCLK3 may constitute an interesting therapeutic target to improve certain neurodegenerative processes.