We investigated the effects of Vietnamese ginseng (VG) extract, VG saponin and the VG major saponin constituent majonoside-R2 on opioid receptor agonist-induced antinociception using the tail-pinch and hot-plate tests in mice and on conditioned fear stress-induced antinociception using the tail-flick test in rats. VG extract (50–100 mg/kg, p.o.), VG saponin (12.5–25 mg/kg, p.o.) and majonoside-R2 (6.2–12.5 mg/kg, p.o.), as well as Panax ginseng extract (PG extract, 50–100 mg/kg, p.o.), dose-dependently attenuated the μ-opioid agonist morphine-induced antinociception in the tail-pinch and hot-plate tests. Moreover, repeated administration of VG saponin and majonoside-R2 suppressed the development of morphine tolerance in the tail-pinch test. VG extract (100–200 mg/kg, p.o.) also dose-dependently blocked the antinociceptive effects of the selective κ-opioid agonist U-50, 488H in the tail-pinch and hot-plate tests, while PG extract (100–200 mg/kg, p.o.) dose-dependently attenuated the U-50,488H-induced antinociception in the hot-plate test but not in the tail-pinch test. VG saponin (6.2–25 mg/kg, p.o.) blocked the U-50,488H-induced antinociception in the tail-pinch test but not in the hot-plate test. Furthermore, VG saponin (25 mg/kg, i.p.) and majonoside-R2 (6.2 mg/kg, i.p.), as well as naloxone (2 mg/kg, i.p.), reversed the tail-flick latency increased by conditioned fear stress in rats. These results indicate that VG and its major saponin constituent, majonoside-R2, attenuate the antinociception caused by opioid agonists and conditioned fear stress.