This study aims to reveal the efficacy and mechanisms of Callerya speciosa total flavonoids (CSF) in the prevention and treatment of osteoarthritis (OA) and chronic bronchitis (CB) based on targeted metabolomics, network pharmacology and experimental verification. Components of CSF from different growth years were analyzed using LC-MS/MS. Network pharmacology and molecular docking were employed to predict the potential active targets of CSF against OA and CB. The efficacy and mechanisms were further verified using cultured human chondrosarcoma SW1353 cells and human normal lung epithelial BEAS-2B cells in vitro. The results showed that 429 flavonoid components were identified in CSF from different growth years, which were divided into four groups (1, 2-3, 6, and 10-15 years), with significant differences in composition and content among these groups. Network pharmacology and molecular docking analyses demonstrated distinct therapeutic associations: the 3-year CSF group exhibited a significant correlation with CB-related targets, whereas the 6-year group showed stronger binding to OA-related targets. Key bioactive flavonoids including hispidulin, genkwanin, wogonin, 5,3'-dihydroxy-7,4'-dimethoxyflavone, and 6,7-dihydroxyflavoneaucubin displayed stable spontaneous binding to core targets. AKT serine/threonine kinase 1 (AKT1) and tumor necrosis factor (TNF) emerged as pivotal hub targets for both OA and CB. In vitro experiments further confirmed that CSF can effectively suppress the expression of TNF and phosphorylated AKT (p-AKT) in inflammatory cell models induced by interleukin-1β (IL-1β) and lipopolysaccharide, in a dose-dependent manner. The results suggest that CSF may alleviate OA and CB by regulating the TNF/AKT signaling pathway.