Focused ultrasound can non-invasively modulate neural activity, but has not yet been optimized for achieving powerful control of natural behaviors and physiological processes. We used fiber photometry coupled focused ultrasound in freely behaving animals to optimize waveform architecture across five different neural populations. For all cell types, we found that low frequency, compressed, high intensity pulsing maximized neural response; inversion of these features caused cell type selective, sustained neural inhibition with particular potency in the beta-gamma range. Examining cortical representation of deep brain stimulation showed that targeting thalamic circuitry resulted in sustained increases somatosensory and visual activity indicating increased engagement. To examine whether the waveform tuning enhanced behavioral outcomes we examined freely moving behavior and found that GABAergic dorsomedial hypothalamus excitation could elicit stimulus locked walking and anxiety behavior capable of overriding natural motivated behavior, whereas non-optimized protocols of equivalent energy or alternate-target exposure resulted in substantially less or no change in behavior. Bidirectional manipulation of the centromedian nucleus activity could increase or decrease head movement through similar total energy delivery indicative of changes in alertness. In examining whether thermal effects could explain neurobehavioral differences, we found that activating protocols induce local cooling in the brain through cyclooxygenase dependent vasoconstriction. Together, these findings demonstrate that, with proper tuning, pure focused ultrasound can exhibit powerful effects on complex behavior and physiological state.