ABSTRACT Objective: Meditation is one of the important tools of psychoneuroimmunology (PNI) that helps in healing and sustenance of good health, also cure and protect from several psychosomatic disorders that result from mental stress. On this concept, the authors have previously provided the attention control mechanism of meditation using an innovative methodology. Presently, the authors have extended the previous attention control mechanism to a more psychoneuroimmunological approach of preksha meditation. Methodology: Present scientific psychoneuroimmunological mechanism of  preksha meditation has been framed using an innovative methodological approach which facilitated the real-time brain imaging (18FDG-PET as an imaging technique) during meditation with EEG recording. Furthermore, this methodological approach allowed us to record electroencephalography (EEG) to affirm meditation objectively while easily avoiding the mutual interference between PET-CT and EEG electrodes. Conclusion: The innovative methodology provides the backbone to frame the psychoneuroimmunological mechanism of preksha meditation. Therefore, present framework provides the scientific evidences to show prefrontal cortex (PFC) acts as a ‘Connector Hub Region’ where all the components of preksha meditation that include attention control, emotional regulation, and altered self-awareness function simultaneously to exert the positive benefits in the maintenance of neuropsychiatric illnesses. Also, it is expected that the present psychoneuroimmunological mechanism will provide a scientific platform for future clinical studies of preksha meditation.   Keywords: Meditation, psychoneuroimmunology, evidence-based research, stress, diseases, health. Clinical Trial Registry: The study was registered at Clinical Trial Registry India (CTRI), CTRI/2009/091/000727.