Evidence of central nervous system (CNS) exogenous opioid effects in humans has been primarily gained through neuroimaging of three participant populations: individuals after acute opioid administration, those with opioid use disorder (OUD), and those with chronic pain receiving opioid therapy. In both the brain and spinal cord, opioids alter processes of pain, cognition, and reward. Opioid-related CNS effects may persist and accumulate with longer opioid use duration. Meanwhile, opioid-induced benefits versus risks to brain health remain unclear. This review article highlights recent accumulating evidence for how exogenous opioids impact the CNS in humans. While investigation of CNS opioid effects has remained largely disparate across contexts of opioid acute administration, OUD, and chronic pain opioid therapy, integration across these contexts may enable advancement toward effective interventions.