Context:Anxiety disorders are chronic, common, and often comorbid. There is an unmet need in its treatment. Aripiprazole and hydroxyzine are well-known therapeutic options used as monotherapy in clinics. They have different mechanisms and site of actions.Aim:The objective of the present study was to evaluate the anxiolytic effect of aripiprazole and hydroxyzine in combination.Materials and Methods:Swiss albino mice (male) received treatment of 5% of Tween 80 in 0.9% saline (10 ml/kg; control group), “aripiprazole alone” (1 mg/kg), “hydroxyzine alone” (3 mg/kg), and aripiprazole (0.5 mg/kg) + hydroxyzine (1.5 mg/kg) through the intraperitoneal route.Results:The in vivo outcomes (elevated plus maze, light/dark transition, and marble burying tests) of hydroxyzine monotherapy-treated group showed a significant anxiolytic activity. The combination-treated group was found to be better than control and aripiprazole-treated groups. The combination-treated group showed a significant increase in the level of serotonin in different brain regions as compared to aripiprazole-treated group but not better than the hydroxyzine group. The in vitro results were in compliance with the in vivo results. The combinational approach was found to be beneficial in anxiolytic treatment as compared to aripiprazole monotherapy. However, hydroxyzine showed better anxiolytic activity when compared to control, aripiprazole monotherapy, and combination groups.Conclusions:The anxiolytic effect of combination-treated group was found to be better than aripiprazole monotherapy and lesser than hydroxyzine monotherapy.