Sensing and regulating intracellular levels of calcium are essential for proper cellular function. In neurons, calcium sensing plays important roles in neuronal plasticity, neurotransmitter release, long-term synapse modification and ion channel activity. Neuronal calcium sensor-1 (NCS-1) is a member of the highly conserved neuronal calcium sensor family. Although NCS-1 has been associated with psychiatric conditions including autism, bipolar disorder and schizophrenia, it is unclear which role NCS-1 plays in behavior. To understand the involvement of NCS-1 in psychiatric conditions, we provided a comprehensive behavioral characterization of NCS-1 knockout (KO) mice. These mice grow and develop normally without apparent abnormalities in comparison to wild type littermates. However, open field showed that NCS-1 deficiency impairs novelty-induced exploratory activity in both KO and heterozygote (HT) mice. Moreover, NCS-1-deficiency also resulted in anxiety- and depressive-like behaviors as demonstrated by elevated plus maze, large open field, forced swim and tail suspension tasks. Furthermore, based on spontaneous object recognition test, non-aversive long-term memory was impaired in NCS-1 KO mice. In contrast, neither social behavior nor a kind of aversive memory was affected under NCS-1 deficiency. These data implicate NCS-1 in exploratory activity, memory and mood-related behaviors, suggesting that NCS-1 gene ablation may result in phenotypic abnormalities associated with neuropsychiatric disorders.