In the present experimental work, we investigate the protective potential of standardized Momordica charantia L fruit extract [gallic acid (GA) 6%; > 8% bitters {momordicosides K (3%) and L (2%); and momordicines I (2%) and II (3%)}] (MC) comparable to its marker compound gallic acid in chemo-toxic neuropathy induced by vincristine [75 μg/kg intra-peritoneal (i.p.) for 10 consecutive days] in rats. An array of behavioral examinations was carried out on days 1st, 12th and 21st, followed by various biochemical and histopathological studies at the end. Vincristine significantly induced cold and dynamic mechanical allodynia, mechanical and heat hyperalgesia; functional deficit in walking and a rise in the levels of TNF-α, IL 6, mitochondrial complexes, myeloperoxidase (MPO), thio-barbituric acid reactive substances (TBARS), and nitrite along with decrease in glutathione (GSH). Administration of MC [400 and 800 mg/kg, per oral (p.o.)], GA (30 mg/kg, p.o.) and gabapentin (100 mg/kg, p.o.) attenuated the vincristine induced behavioral and biochemical changes. MC demonstrated superior antinociceptive activity in comparison to GA. Histopathological evaluation also divulged defending the effects of MC. Pretreatment of saclofen (1 mg/kg, i.p.), picrotoxin (1 mg/kg, i.p.) upturned the antinociceptive action of MC, but ingestion of GABA (100 mg/kg, i.p.) potentiated the action of MC. Additionally, pretreatment with l -arginine [nitric oxide (NO) donor; 100 mg/kg, i.p.] inverted the antinociceptive action of MC; whereas, aminoguanidine (iNOS inhibitor) and 7-nitroindazole (nNOS inhibitor) potentiated it. Besides this a PPARγ antagonist BADGE did not amend the effect of MC. Corroboratively, the attenuating effect of MC in vincristine induced neuropathy is attributed to its modulating action on GABAergic system along with antimitotoxic, NOS inhibition, anti-inflammatory and anti oxidative activities.