Saponins are valuable principles found in various herbal medicine with pharmaceutical, cosmetical and nutraceutical merits. In this study, we evaluated the protective role of saponin fraction (Cl-SF), prepared from Codonopsis lanceolata, an ethnopharmacologically famous plant in Korea, China and Japan, on water immersion stress-induced liver damage and radical generation. Cl-SF clearly decreased the up-regulated levels of serum glutamate-oxalacetate transaminase and glutamate-pyruvate-transaminase induced by water-immersed stress conditions. Furthermore, Cl-SF seemed to block the stress-induced radicals. Thus, Griess and DPPH assays revealed that Cl-SF significantly suppressed both radical generation in sodium nitroprusside-treated RAW264.7 cells and nitric oxide production in LPS-treated RAW264.7 cells. Therefore, these results suggest that Cl-SF may be considered as a promising stress-regulatory principle with radical scavenging actions.