Cognitive control, the coordination of executive functions including working memory, response inhibition, error monitoring, and decision-making, is critical for navigating human life, and cognitive control impairment is a feature of myriad debilitating conditions. Cognitive control is hypothesized to arise from interactions among large-scale brain networks, but mechanisms underlying network dynamics are largely unknown. Accumulating functional studies in model animals suggest the claustrum, a subcortical brain structure with unparalleled cortical connectivity, supports the initiation of multiple brain networks. However, few tests of human claustrum function have been performed despite the neuroimaging field’s established network analysis tools and the opportunity to incorporate clinical samples. A potential barrier to acquiring valid claustrum BOLD signal with standard MRI hardware, partial volume effects, was addressed, and a novel method to protect against partial volume effects in task fMRI was developed. In publicly available datasets of healthy participants, increased claustrum BOLD signal was associated with increased brain-wide network activity in multiple memory tasks evoking a wide range of network states. Structural and effective connectivity findings were consistent with excitatory claustrum projections to recruited cognitive control network regions, and results distinguished claustrum from other regions implicated in cognitive control network mechanisms. Comparisons between healthy participants and patients with chronic pain, which is associated with cognitive control deficits and altered network activity, observed claustrum activation at the onset of a difficult cognitive task and acutely painful stimuli, with patients exhibiting increased right claustrum activity in both conditions. Patients recruited an additional, pain-sensitive cortical region during cognitive task processing, and structural and effective connectivity analyses were consistent with increased excitatory influence of right claustrum on this region in patients than controls. The collected results provide empirical support for a claustrum role in cognitive control network initiation and raise the possibility of the claustrum as a future therapeutic target for neuropsychiatric disorders characterized by cognitive impairment and cortical network abnormalities.