Chlorella pyrenoidos polysaccharides (CPPs) are the main active components of Chlorella pyrenoidos. They possess beneficial health properties, such as antioxidant, anti-inflammatory, and immune-enhancing. This study aims to investigate the protective function and mechanism of CPPs against high-temperature stress injury. Results showed that supplementation with 20 mg/mL CPPs significantly extended the lifespan of Drosophila melanogaster under high-temperature stress, improved its motility, and enhanced its resistance to starvation and oxidative stress. These effects were mainly attributed to the activation of Nrf2 signaling and enhanced antioxidant capacity. Additionally, it has been discovered that CPPs supplementation enhanced Drosophila resilience by preventing the disruption of the intestinal barrier and accumulation of reactive oxygen species caused by heat stress. Overall, these studies suggest that CPPs could be a useful natural therapy for preventing heat stress-induced injury.