<p>Microglial cells play a pivotal role in the different CNS related conditions as they have the power to destruct as well protect the Central Nervous System. Depending on the environment they are in, they respond to different stimuli and carry out a function. Majority of the cases, the microglial cells are activated which cause inflammation to a very large extent and for a prolonged period of time which causes the various signs and symptoms of the neurodegenerative disorders. Cannabinoid Type-2 (CB2) receptor crosstalk is a key modulator of microglial plasticity, influencing both pro-inflammatory and anti-inflammatory states in the brain. Activation of CB2 receptors in microglia can suppress neurotoxic inflammation, promote anti-inflammatory phenotypes, and facilitate microglial migration and environmental surveillance. By shifting microglial polarization away from pro-inflammatory states, CB2 stimulation helps control neuroinflammation and supports tissue repair in neurodegenerative and neuroinflammatory conditions. This intricate crosstalk highlights CB2 as a promising therapeutic target for managing central nervous system dysfunctions mediated by microglial activity. The present review discusses CB2 receptor crosstalk and its role in microglial plasticity and neuroinflammation.</p> Graphical abstract <p></p>