Promoting neurogenesis is a promising strategy for the treatment of cognition impairment associated with Alzheimer's disease (AD). Ganoderma lucidum is a revered medicinal mushroom for health-promoting benefits in the Orient. Here, we found that oral administration of the polysaccharides and water extract from G. lucidum promoted neural progenitor cell (NPC) proliferation to enhance neurogenesis and alleviated cognitive deficits in transgenic AD mice. G. lucidum polysaccharides (GLP) also promoted self-renewal of NPC in cell culture. Further mechanistic study revealed that GLP potentiated activation of fibroblast growth factor receptor 1 (FGFR1) and downstream extracellular signal-regulated kinase (ERK) and AKT cascades. Consistently, inhibition of FGFR1 effectively blocked the GLP-promoted NPC proliferation and activation of the downstream cascades. Our findings suggest that GLP could serve as a regenerative therapeutic agent for the treatment of cognitive decline associated with neurodegenerative diseases.•G. lucidum polysaccharides (GLP) improve cognition in transgenic AD mice•GLP promote neural progenitor proliferation and self-renewal to enhance neurogenesis•GLP potentiate FGFR signalingG. lucidum is a revered medicinal herb for promoting health. Pei and colleagues found that the polysaccharides from G. lucidum (GLP) promoted neural progenitor proliferation to enhance neurogenesis and ameliorated cognition deficits in transgenic Alzheimer's disease model mice. These findings suggest that GLP could serve as a regenerative therapeutic agent for the treatment of cognitive decline associated with neurodegenerative diseases.