Activatable phototherapeutic agents (PTA) in one system with synergistic gas therapy (GT) and photothermal therapy (PTT) hold great promise for highly efficient tumor treatments. In this study, an activatable multifunctional platform with photothermal conversion “turn on” features via nitric oxide (NO) release for synergistic GT and PTT was rationally designed using an aryl N-nitrosamine (NO-donating unit) functionalized aza-BODIPY framework (S–NO). As expected, after NO release from S–NO, the product (Red-S) showed obviously enhanced heat production performance under a longer excited wavelength via improved near-infrared light absorption and decreased fluorescence emission. Furthermore, water-soluble and biocompatible S–NO nanoparticles (S–NO NPs) with negligible dark cytotoxicity successfully suppressed tumor growth and enhanced the survival rate of mice via synergistic GT and PTT under the guidance of multimode imaging. The study offered rational guidance to design better platforms for synergistic tumor treatments and validated that S–NO NPs can act as potential PTAs in biological applications.