Heart-brain interaction is widely highlighted as a contributor to several cardiovascular and neurodegenerative diseases. Great interest has been focused on miRNAs as one of the possible molecular mechanisms of heart-brain interaction. Therefore, we aimed to investigate the potential neuroprotective effects of policosanol (POL), a commonly used hypocholesterolemic agent, versus cognitive impairment and neuronal damage in a post-myocardial infarction (MI) rat model. Additionally, we aimed to explore the molecular mechanisms through which POL may ameliorate this damage through its effects on miRNA-1 and its target genes. Post-MI-induced neuronal damage was induced in rats by isoproterenol (ISO) (100 mg/kg) given as two subcutaneous injections separated by 24-h interval. Then, rats were treated with POL (50 mg/kg/day, orally) for 4 weeks. Post-MI-induced cognitive dysfunction was characterized by the increased locomotor activity and the decreased spatial cognition ability in Y-maze test. Hippocampal miRNA-1 expression was increased following MI and thereby, the hippocampal BDNF mRNA expression along with its contents of TrkB and CREB were decreased. Additionally, the hippocampal FZD7 mRNA expression along with active β-catenin and NeuroD1 contents were decreased. Moreover, the cortical mRNA expression of HSP70 and its contents of TPPP/P25 and BCL-2 were decreased, but cortical contents of BAX and caspase-3 were increased. Treatment with POL ameliorated these changes resulting in the alleviation of the post-MI-mediated neuronal damage and cognitive dysfunction. Our findings suggest a novel insight into one of the possible molecular mechanisms of POL neuroprotective effects versus Post-MI-induced neuronal damage and cognitive impairment at the miRNA level.