Parkinson disease (PD) is a neurodegenerative disorder of the motor activity of the brain, regulated by dopaminergic neurons of substantia nigra, resulting in an increased density of histaminergic fibers. This study was aimed to evaluate the effects of H1 antagonist’s ebastine and levocetirizine in PD per se and in combination. Animals were divided into 9 groups ( n = 10). Group 1 received carboxymethyl cellulose CMC (1 mL/kg). Group II was treated with haloperidol (1 mg/kg) (diseased group). Group III was treated with levodopa/carbidopa (levo 20 mg/kg). Groups IV and V were treated with ebastine at dose levels of 2 and 4 mg/kg, respectively. Groups VI and VII were treated with levocetirizine at dose levels of 0.5 and 1 mg/kg, respectively. Group VIII was treated with ebastine (4 mg/kg) + levo (20 mg/kg) in combination. Group IX was treated with levocetirizine (1 mg/kg) + levo (20 mg/kg). PD was induced with haloperidol (1 mg/kg iv, once daily for 23 days) for a duration of 30 min. Behavioral tests like rotarod, block and triple horizontal bars, actophotometer, and open field were performed. Biochemical markers of oxidative stress, i.e., SOD, CAT, GSH, MDA, dopamine, serotonin, and nor-adrenaline and nitrite, were determined. Histamine, mRNA expression of α-synuclein, and TNF-α level in the serum and brain of mice were analyzed. Endogenous biochemical markers were increased except mRNA expression of α-synuclein, which was reduced. In combination therapy with the standard drug, ebastine (4 mg/kg) significantly improved the cataleptic state and dopamine levels, but no significant difference in the renal and liver functioning tests was observed. This study concluded that ebastine (4 mg/kg) might work in the treatment of PD as it improves the cataleptic state in haloperidol-induced catalepsy.