Activation of brain regions that make up the mirror neuron system (MNS) is thought to reflect processing and perceiving behavior, action, and intentionality of other organisms. Sensing and perceiving motor behavior in others is an important component of understanding and participating in social interactions. Children with chromosome 22q11.2 deletion syndrome (22q11.2DS) are diagnosed with serious medical, cognitive, and socio-emotional symptoms. Atypical development and function of the MNS may underpin some aspects of socio-emotional impairment and autism spectrum disorder (ASD)-like symptomology reported. This study of the MNS investigates differences in activation in the operculum, sensorimotor areas, and basal ganglia (BG) in children with 22q11.2DS compared to typically-developing (TD) controls. Twenty-nine children (22q11.2DS: n=15; TD: n=16) between ages 7-16 viewed videos of a human hand manipulating various household objects during a functional magnetic resonance imaging (fMRI) scan. In Analysis 1, children with 22q11.2DS had less extensive brain activation than TD children in the operculum, sensorimotor areas, and BG. In Analysis 2, children with 22q11.2DS had the same results as Analysis 1 with the exception of sensorimotor areas not being highly active in either group. In both analyses, fMRI signal change from baseline to video did not differ significantly between groups. Processing efficiency in children with 22q11.2DS may be lower or more variable when compared to TD peers. This is the first study comparing children with 22q11.2DS to TD peers specifically looking at MNS activation within the operculum region to assess higher cognitive functioning, somatosensory cortex for sensory interpretation, and basal ganglia for gross motor activity. Future studies should compare brain activation between children with ASD and those with 22q11.2DS during an MNS task as the next step to further clarify the origin of ASD symptoms reported in this population.