Piperine, the major pharmacological ingredient of pepper, can delay the procession of neuropharmacological effects, but its effects and mechanisms on Parkinson's disease dementia (PDD) mice is still unclear, we investigated whether piperine could help treating PDD mice. Here, PDD mice were randomly divided into eight groups (n = 12/group): a normal control group, a PDD model group, a madopar group, an autophagy inhibitor group, an autophagy activator group, and groups receiving low, medium or high doses of piperine respectively. The normal control and PDD model mice were injected with saline. Treatments were administered to the mice once per day continuously for 30 days. The behavioral tests were assessed. Dopamine (DA), Monoamine Oxidase-B (MAO-B), DOPA decarboxylase (DDC), β-secretase, acetylcholinesterase (AChE), amyloid β42(Aβ42), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels were detected. α-synuclein (α-syn), tyrosine hydroxylase (TH), HSP90, Beclin-1, LC3B, p62 mRNA levels and miRNA-99a-5p expression were determined. Neuronal histology was observed. The behavior of PDD mice improved significantly after peperine treatment compared with the PDD model mice. In addition, our results also showed that peperine treatment increased DA, TH, DDC and p62 levels, decreased MAOB, β-secretase, AChE, Aβ42, TNF-α, IL-6, Beclin-1 and LC3B levels, and down-regulated α-syn, HSP90, Beclin-1, LC3B mRNA levels and miR-99a-5p expression. These findings suggest that piperine may reduce the expression of mmu-miR-99a-5p and autophagy-related factors (HSP90, Beclin-1, LC3B and p62) to alleviate the neurological impairment of PDD mice, which is shown to slow down the process of DA metabolism and Aβ production and resist neuroinflammation.