Neurensin-2 (Nrsn2) is a neuro-specific gene linked to neurodevelopmental disorders and has recently been reported to function as a bidirectional emotional regulator, highlighting its molecular roles in the nervous system. However, the connections between Nrsn2, brain architecture, and functionality remain to be fully elucidated. Our study utilized 11.7 T multimodal magnetic resonance imaging (MRI) to assess the impact of Nrsn2 gene knockout on the brain’s microstructure, regional functional activity, and network connectivity during different developmental phases in mice. We observed significant changes in the functional brain network connectivity of Nrsn2−/− mice without marked differences in brain microstructure or regional activity. These changes were particularly pronounced in sensory-related areas, such as the gustatory and auditory systems, in both juvenile and adult specimens. Previous studies have correlated the enhanced Default Mode Network (DMN) with depression, and Nrsn2 knockout has been associated with stress resilience. Our findings further revealed reduced connectivity in various DMN regions in adult Nrsn2−/− mice, suggesting a potential link to increased stress tolerance. Moreover, the sensory system’s critical role in environmental perception implies that alterations in network connectivity due to Nrsn2 knockout could affect the processing and integration of external inputs, thereby influencing emotional experiences.