Light therapy red and near-infrared (NIR) irradiation is currently actively utilized in clinics and extensively studied due to the positive outcomes it yields. However, the previously explored interactions between light and cells are associated with cellular pathways linked to the cytochrome-c-oxidase photoacceptor, reactive oxygen species and calcium ion receptors activated by light-induced depolarization of the cellular membrane. To identify new molecular mechanisms of transcranial photobiomodulation therapy (tPBMT) on neuronal cells in vivo, we conduct the first-ever next-generation whole RNA sequencing (RNA-Seq) of the cortex and hippocampus of BALB/c mice following an 808 nm light treatment with a 30-day course of daily 1-hour sessions (36 J/cm2 at 10 mW/cm2). RNA-Seq of over 30,000 mRNA molecules reveals a significant dysregulation of transcription after tPBMT. Transcriptional alterations are found in 1,005 genes in the hippocampus and 1,482 genes in the cortex. Pathway-gene enrichment network analysis identifies 50 pathways involving these genes. The constructed disease-gene network highlights potential diseases in which gene expression may be changed after tPBMT. Additionally, light also modulates the transcription of key genes identified as the main risk factors for AD, involved in APP processing or associated with oxidative stress, inflammation and apoptosis, thereby supporting AD development.