Red light is useful for optogenetic control of various protein activities in mammalian deep tissues due to its high tissue penetration, low invasiveness, and low light scattering. However, technology that enables for the optogenetic manipulation using red light remains elusive. Here we develop a red light-activatable, semi-synthetic photoswitch, named MagRed. MagRed is composed of a red light-absorbing bacterial phytochrome incorporating a mammalian endogenous chromophore, biliverdin, and its photo-state-specific de novo synthetic binder. MagRed allows us to reassemble split-proteins using red light and thereby develop a red light-activatable Cre recombinase, which is applicable for mammalian deep tissues. Additionally, we take advantage of MagRed to develop red light-inducible transcription system based on the CRISPR-Cas9 system, enabling for high induction (up to 378-fold) of multiple user-defined endogenous target genes. With high versatility and regulatability, MagRed provides a powerful technology that easily facilitates optogenetics applications for a variety of biological research areas.