Major Depressive Disorder (MDD) is a serious psychiatric disorder characterized by persistent sadness and loss of interest. Several studies have identified altered connections between different brain regions in patients with MDD compared to healthy controls. In this study, we extensively examined whole-brain functional connectivity impairments in MDD. In addition, we also examined whether the brain’s connector hubs, specialized regions with connections to multiple brain networks and considered critical for the brain’s integrative functions, are involved in this disorder. We used a network metric called functional connectivity overlap ratio (FCOR) estimated from resting-state functional MRI to examine connectivity alterations across several large-scale functional brain networks in patients with MDD compared to healthy controls. MRI data from patients with MDD (N = 251) and age- and sex-matched health controls (N = 251) from a publicly available data repository were used in the analysis. The results revealed widespread connectivity alterations of several large-scale functional brain networks in MDD patients. Specifically, the sensorimotor, basal ganglia, salience, and auditory networks showed connectivity alterations across widespread brain regions in the patient group compared to control group. Connector hub regions located primarily in bilateral sensorimotor cortex, right paracentral lobule, and bilateral thalamus also showed significantly lower connections with multiple brain networks. Taken together, these findings highlight the involvement of connector hub regions in the pathophysiology of MDD. Their impairment affects the normal functions of multiple networks and potentially leads to the different clinical manifestations observed in this disorder.