Major depressive disorder (MDD) is a highly prevalent and disabling psychiatric condition characterized by varying degrees of affective, cognitive, somatic, and psychomotor symptoms. Neuroimaging studies have identified dysfunctional connections of several large-scale brain networks in MDD that have been associated with its various symptoms. Given the involvement of multiple brain networks, we hypothesized that MDD could be driven by connectivity impairments of key regions involved in the brain’s integrative processes called connector hubs. MRI data from 255 patients with MDD and 255 matched healthy controls were used in the analysis. A network metric called functional connectivity overlap ratio, computed from resting-state functional MRI, was used to identify affected hub regions. Our results showed that connector hubs located in the sensorimotor cortex, thalamus, cerebellum, and limbic regions exhibited altered connections across multiple networks in patients compared to controls. Specifically, sensorimotor connector hubs had significantly less connections with primary processing (sensorimotor, visual, and auditory), default mode, and visuospatial networks, but more widespread connections with the anterior salience and basal ganglia networks. Cerebellar and thalamic connector hubs exhibited less connections with the core neurocognitive (default mode, executive control, and salience), language, and basal ganglia networks, whereas limbic connector hubs had impaired connections with salience, language, and basal ganglia networks. Additionally, some of these altered connections correlated with depression scores in patients. Together, these findings suggest that MDD is characterized by a more widespread impairment of the brain’s integrative functions involving sensory, motor, cognitive, and affective processes, reflecting its diverse symptoms.