Polygonum cuspidatum, a key source of resveratrol and polydatin, faces cultivation challenges due to drought, which impairs plant growth and bioactive compound synthesis. This study investigated the effects of inoculating P. cuspidatum with arbuscular mycorrhizal fungus Funneliformis mosseae on its drought resilience and bioactive compound accumulation under drought stress. Although drought significantly reduced mycorrhizal colonization rates, inoculation with F. mosseae under drought still significantly enhanced aerial growth (plant height, stem diameter, leaf number, and aboveground biomass), phosphorus (P) levels, nitrogen balance index, and root development (total length, projected area, surface area, and volume). Drought stress profoundly elevated leaf superoxide dismutase, peroxidase (POD), and catalase (CAT) activities and proline levels, while F. mosseae further amplified these enzyme activities, particularly boosting POD and CAT under well-watered conditions and all three antioxidant enzymes under drought conditions, followed by a substantial decrease in proline levels. Drought diminished the levels of four active components (polydatin, resveratrol, aloe-emodin, and physcion), while F. mosseae differentially enhanced the levels of specific medicinal components, as evidenced by an increase in polydatin, resveratrol, aloe-emodin, and physcion under well-watered and an elevation in polydatin, resveratrol, aloe-emodin, and chrysophanol under drought. Gene expression analysis revealed that drought triggerred the down-regulated expression of resveratrol biosynthesis genes, while F. mosseae upregulated all six tested genes under well-watered conditions and selectively enhanced PcCHS1, PcCHS12, PcRS11, and PcCRS1 under drought conditions. This emphasizes that arbuscular mycorrhizal fungal inoculation is a promising strategy to enhance plant establishment and bioactive compound accumulation of P. cuspidatum in drought-prone environments.