This study aimed to investigate the transformation of Polygonatum cyrtonema Hua (PCH) by lactic acid bacteria (LAB), including Lactobacillus plantarum (P-5, Z-2, and 28–1) and Lactobacillus pentosus P-7. LAB-fermented PCH (FPCH) altered sugar and acid profiles, along with increasing total phenolics, flavonoids, and saponins. FPCH developed a more complex and pleasant aroma profile, marked by increased key flavor compounds such as 2-undecanone and β-damascenone; meanwhile, astringency and green/herbal off-odors, represented by epigallocatechin (EGCG), were reduced. LAB fermentation increased naringin and 4-hydroxybenzoic acid contents, enhancing antioxidant capacity. Notably, FPCH fermented by L. plantarum P-5 (P-5-FPCH) protected PC12 cells against oxidative stress and further alleviated uric acid-induced oxidative injury in HK-2 renal tubular epithelial cells. In hyperuricemic mice, P-5-FPCH reduced serum uric acid levels and alleviated renal injury, likely by increasing caffeic and cinnamic acids. Transcriptome analysis of LAB revealed the above-mentioned related genes ( sacA, pyk, and adh ). Overall, LAB fermentation offers a safe and promising bioprocessing strategy to enhance the quality and bioavailability of PCH.