Background: Serotonin and norepinephrine are important neurotransmitters involved in pain inhibition in descending pain inhibitory tracts. Venlafaxine being an antidepressant exerts its mechanism mainly by inhibiting reuptake of serotonin and norepinephrine like Tramadol. The objectives were to study the antinociceptive activity of Venlafaxine and its comparison with Pethidine.Methods: A total of 32 Swiss albino mice were divided into 4 groups with 8 animals in each group. Group 1 received normal saline as control in dose of 5ml/kg i.p, Group 2 received Pethidine as standard in dose of 30mg/kg s.c, Group 3 received Venlafaxine as in dose of 10mg/kg i.p and Group 4 received Venlafaxine in dose of 22.5mg/kg. Tail flick test and hot plate test were used for evaluating antinociceptive activity. All animals were subjected to the above mentioned tests before and 30 minutes after the administration of the drugs. Results were subjected to suitable statistical analysis.Results: The results from the above mentioned tests showed that Venlafaxine in dose of 10mg/kg showed significant antinociceptive activity as compared to normal saline (p <0.05) but was not comparable to Pethidine (p >0.05). Venlafaxine in dose of 22.5mg/kg showed significant antinociceptive activity as compared to normal saline (p <0.05) and activity was comparable to Pethidine.Conclusions: Venlafaxine in both the doses showed significant antinociceptive activity in acute models of pain in animals.