Cancer gas therapy is just in an early stage of research and development. Several important gasotransmitters have proven their therapeutic potentials, but handling, delivery and controlled release of these gases remain very challenging for therapeutic purposes. This research develops a versatile nanosystem that is capable of delivering carbon monoxide (CO) gasotransmitter in the form of photo-responsive carbon monoxide-releasing molecule (CORM) for targeted cancer therapy. The core-shell upconversion nanoparticles (UCNPs) were designed to transfer bio-friendly low energy near infrared (NIR) light to ultraviolet (UV) light and trigger CO release from the loaded CORM. The synthesized delivery system demonstrated its ability to mediate the sustained release of CO upon 808 or 980 nm NIR light excitation. The optimized nanoformulation was efficiently taken up by HCT116 cancer cells and showed dose-dependent cytotoxicity to HCT116 and other cancer cells. Intracellular CO release and subsequent therapeutic action involving ROS production were found to significantly contribute to cell apoptosis. Therefore, the current research demonstrates the potency and efficiency of an NIR-mediated UCNP-based CORM prodrug delivery system for targeted cancer gas therapy.