In a group of 831 participants from the general population in the Human Connectome Project, smokers exhibited low overall functional connectivity, and more specifically of the lateral orbitofrontal cortex which is associated with non-reward mechanisms, the adjacent inferior frontal gyrus, and the precuneus. Participants who drank a high amount had overall increases in resting state functional connectivity, and specific increases in reward-related systems including the medial orbitofrontal cortex and the cingulate cortex. Increased impulsivity was found in smokers, associated with decreased functional connectivity of the non-reward-related lateral orbitofrontal cortex; and increased impulsivity was found in high amount drinkers, associated with increased functional connectivity of the reward-related medial orbitofrontal cortex. The main findings were cross-validated in an independent longitudinal dataset with 1176 participants, IMAGEN. Further, the functional connectivities in 14-year-old non-smokers (and also in female low-drinkers) were related to who would smoke or drink at age 19. An implication is that these differences in brain functional connectivities play a role in smoking and drinking, together with other factors.