Objective: Meditation, a major component of a yoga-based lifestyle, has been implicated in relaxation and is known to reduce stress and anxiety. A plausible mechanism of such relaxing effect is psychoneuroimmunology (PNI), based on a relation and interaction between mind, physical health, and self-healing; that conceptualizes that stress and the emotional state of an individual may play a significant role in increasing vulnerability to diseases. Research to date suggests that meditation may play a vital role in resetting the imbalance between psycho-physical health by modulating the psychoneuroimmunological effects of stress. However, to date, this multi-faceted psychoneuroimmune aspects of meditation has not been completely elucidated. Methodology: On this concept, evidence-based mechanism has been framed for the first time from India to explain the psychoneuroimmunological aspects associated with regular and long-term meditation practice using an innovative 18FDG-PET methodological approach. Conclusion: The innovative methodology provides the backbone to frame the psychoneuroimmunological mechanism of meditation. Therefore, the present mechanism confirms prefrontal cortex (PFC) acts as a ‘Connector Hub Region’ where all the components of meditation that include attention control, emotional regulation, and altered self-awareness function simultaneously to exert the positive benefits in the regulation of cognitive and emotional behavior. Also, this mechanism will help us to understand how a particular pathway fosters brain plasticity to overcome various neuropsychiatric illnesses.