Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme with diverse biological functions in DNA synthesis. Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate‐limiting enzyme involved in NAD+ biosynthesis in mammals. We developed the first chemical tool for optical control of NAMPT and NAD+ in biological systems using photoswitchable proteolysis‐targeting chimeras (PS‐PROTACs). An NAMPT activator and dimethylpyrazolazobenzene photoswitch were used to design highly efficient PS‐PROTACs, enabling up‐ and down‐reversible regulation of NAMPT and NAD+ in a light‐dependent manner and reducing the toxicity associated with inhibitor‐based PS‐PROTACs. PS‐PROTAC was activated under 620 nm irradiation, realizing in vivo optical manipulation of antitumor activity, NAMPT, and NAD+. The first activator‐based photoswitchable proteolysis‐targeting chimera (PS‐PROTAC) was developed for the optical control of NAMPT and NAD+ in biological systems. The novel PS‐PROTAC enabled the reversible regulation of NAMPT and NAD+, resulting in a significant reduction in target‐related toxicity compared to conventional NAMPT degraders or inhibitors. Furthermore, PS‐PROTAC allowed for the in vivo optical manipulation of antitumor activity, NAMPT, and NAD+.