Depression is the most common psychiatric disease characterized by a persistently depressed mood. In patients with major depression, neuroplastic impairments are often observed. The failure rates of antidepressants exceed 30% due to treatment resistance, severe side effects, or prolonged onset of action. There is an absence of fast-acting antidepressants with good biocompatibility. Tetrahedral framework nucleic acid (TFNA), a novel DNA nanodevice, is expected to have extensive application value. Previously, work has examined the biological effect of TFNA on multiple cells types, and TFNA played active roles in neuroprotective and anti-inflammatory. To explore a new research direction for neuroplasticity and a potential mechanism for depression remedies, we tried to define the effects of TFNA on neuroplasticity. The results in vitro showed that TFNA alleviated cytotoxicity and disinhibited proliferation inhibition induced by corticosterone (CORT). In histological studies and behavioral tests, TFNA reduced synapse loss, improved neuronal atrophy, and increased cell number/vitality, thus resulting in improved depression-like behaviors in CORT-induced mice models in the early stages without a toxic effect. Proteins associated with synapse formation and PI3K-AKT-mTOR pathways were also explored to confirm these findings further. Overall, this work demonstrated the positive neuroplastic and therapeutic potential of TFNA for depression.