Loss of neurons and decline in motor and cognitive functions are the major hallmarks of the neurodegenerative disorders. Over a long time span, focus has been given to the intricate associations of neurons and immune system which is a bi-directional approach. Neuroimmune system which is also highly associated with the gut anatomy has a major role to play in the therapeutic intervention of neurodegenerative disorders. Herein, we have attempted to review the key aspects of gut and neuroimmune system by understanding their anatomy, signaling cascades, innate and adaptive immune responses, and molecular basis of neuroimmune interactions. Moreover, focus has been laid on the dualistic role of microglia which are the resident immune cells and possess neuroprotective as well as neurotoxic roles to play. Furthermore, the emerging immunotherapies and their clinical significance in the decline of neurodegenerative disorders has been highlighted. Altogether, representing the dynamic and complex interplay between immune and nervous system having gut as the major player. This has relevance in developing novel and effective therapies.