L-dopa-induced dyskinesia (LID) is an incapacitating complication of long-term administration of L-dopa therapy that commonly affects patients with Parkinson’s disease (PD) due to the widespread use of the causative drug. Herein, we investigated the therapeutic potential of sitagliptin, a drug used to treat type 2 diabetes mellitus, to treat LID. 6-hydroxydopamine (6-OHDA) was unilaterally injected into the left side of the substantia nigra pas compacta to induce a mouse model of PD. After four weeks of 6-OHDA induction, L-dopa was administered with or without sitagliptin for 11 consecutive days. LID was monitored using abnormal involuntary movement (AIM) scoring, conducted on days 5 and 10 of L-dopa treatment. Comparative proteomic analysis was performed on the 6-OHDA-lesioned striatum by comparing groups treated with vehicle + L-dopa and sitagliptin + L-dopa. Changes in the expression of Ndufb2 and Arc, which showed the greatest increase or decrease, were validated using western blotting and RT-PCR analysis. Sitagliptin combined with L-dopa significantly attenuated AIM scores in 6-OHDA-lesioned mice. The protein level of Ndufb2 was increased by the co-administration of sitagliptin and L-dopa in both unlesioned and 6-OHDA-lesioned striata compared with the administration of L-dopa alone. The expression levels of FosB and c-Fos, and Arc were suppressed by the co-administration of sitagliptin and L-dopa in the 6-OHDA-lesioned striatum. These findings suggest that sitagliptin may have therapeutic potential for incapacitating complications of long-term L-dopa use in patients with PD.