Optogenetics has been developed to control the activities and functions of neural circuits with high cell-type specificity and spatiotemporal resolution. However, current optogenetic tools generally rely on visible light with poor tissue penetration ability that does require invasive optical fiber devices to deliver visible light into deep inside brain tissue. These often result in a series of side effects, such as tissue damage and restrict free movement of animals. Fortunately, upconversion nanoparticles (UCNPs)-mediated optogenetic systems facilitate the optogenetic regulation in complex living systems. In this review, the recent advances on design strategies of UCNP-mediated wireless optogenetics in biomedical research are summarized and the future perspectives for refining and advancing UCNP-mediated wireless optogenetics into in vivo for remote therapy are proposed.