We have developed a robust functional ultrasound (fUS) imaging pipeline to measure drug‐ induced changes in brain activation and functional connectivity (FC) patterns, through the intact skull, in awake and behaving mice. We report that major opioid and cannabinoid drugs lead to highly‐reproducible, dose‐ and time‐dependent reorganization of brain activation and FC patterns. While displaying individual spatio‐temporal profiles, which parallel the development of behavioral parameters such as analgesia, all these drugs lead to drug‐specific dysconnectivity fingerprints between cortical, hippocampal and subcortical regions. These effects are sensitive to pharmacological and genetic receptor inactivation, but are independent from animal movement and from global changes in brain perfusion. Our results both suggest the reorganization of inter‐regional connectivity as an important brain effect of opioids and cannabinoids and validate a new approach in the development of neuropsychiatric drugs, with the potential of identifying compounds with improved pharmacological profiles.