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Optogenetics is among the most widely employed techniques to manipulate neuronal activity. However, a major drawback is the need for invasive implantation of optical fibers. To develop a minimally invasive optogenetic method that overcomes this challenge, we engineered a new step-function opsin with ultra-high light sensitivity (SOUL). We show that SOUL can activate neurons located in deep mouse brain regions via transcranial optical stimulation and elicit behavioral changes in SOUL knock-in mice. Moreover, SOUL can be used to modulate neuronal spiking and induce oscillations reversibly in macaque cortex via optical stimulation from outside the dura. By enabling external light delivery, our new opsin offers a minimally invasive tool for manipulating neuronal activity in rodent and primate models with fewer limitations on the depth and size of target brain regions and may further facilitate the development of minimally invasive optogenetic tools for the treatment of neurological disorders. • We introduce SOUL, a new step-function opsin with ultra-high light sensitivity • SOUL activates deep mouse brain and change behaviors via transcranial illumination • SOUL activates macaque cortical neurons via illumination through the dura • Transdural activation of SOUL in macaques induces oscillatory activity reversibly Is it possible to turn on and off neurons inside the brain by shining light from outside the head? Now it is. SOUL, a newly developed light-responsive molecule, is so sensitive to light that it can activate neurons inside the brain of mice and monkeys with external illumination. [ABSTRACT FROM AUTHOR]