Major depressive disorders (MDD) is one of the most common mental illness in the world. Recently, brain m6A /m (fat mass- and obesity-associated gene Fto) was found that exerted an important role in regulating gene expression involved in stress related depression. However, the potential mechanism of Fto on depression still remains elusive. This study investigated the role of Fto and its downstream signaling pathway in hippocampus on chronic restraint stress induced depressive-like behaviors. C57BL/6 mice weighing 20-22 g were randomly divided into 4 groups (Control, Control + Fto-ov, Stress, Stress + Fto-ov). Mice were exposed to chronic restraint stress for 3 consecutive weeks to induce depression model. Mice in the Fto-ov groups were stereotaxic injected with Recombinant Adeno-associated Virus lentivirus (Fto) in hippocampus followed by stress procedure. Depressive-like behaviors were detected after stress procedure. Western blot was used to test hippocampal Fto, p-CaMKII and p-CREB expression. Post synaptic density protein 95 (PSD95) and synaptophysin levels were detected by PCR. Golgi-Cox staining was used to appraise dendritic spine density and branches. Synaptic morphology in hippocampus was determined by electron microscopy. We demonstrated that chronic restraint stress induced depressive-like behaviors, decreased protein expression of Fto, p-CaMKII and p-CREB, reduced levels of synaptic plasticity markers (synaptophysin and PSD95) in hippocampus. Moreover, chronic restraint stress led to synaptic morphology alterations (reduced dendritic spine density and number of branches; thinned postsynaptic density). However, these molecules changes and morphology alterations were reversed by stereotaxic injected recombinant adeno-associated Fto-overexpression virus in hippocampus. This study found that the modulation of Fto on CaMKII/CREB signaling pathway plays a key role in hippocampal synaptic plasticity, and then ameliorated chronic restraint stress induced depressive-like behaviors.